Drug Delivery System and Methods of Treating Open Angle Glaucoma and Ocular Hypertension

ABSTRACT

A method of decreasing intraocular pressure (IOP) in an eye of a patient in need thereof includes implanting a first lacrimal implant through an upper punctum and into an upper lacrimal canaliculus of the eye of the patient. The method may further comprise implanting a second lacrimal implant through a lower punctum and into a lower lacrimal canaliculus of the eye of the patient, and releasing, on a sustained basis a therapeutically effective amount of an intraocular pressure-reducing therapeutic agent.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. Ser. No. 13/598,573,filed Aug. 29, 2012, which claims priority to U.S. Provisional PatentApplication No. 61/528,736, filed on Aug. 29, 2011, and U.S. ProvisionalPatent Application No. 61/644,397, filed on May 8, 2012, the disclosuresof each of which are incorporated herein by reference in their entiretyfor all purposes. This application claims the benefit under 35 U.S.C.1.19(e) of U.S. Provisional Patent Application No. 61/642,287, filed May3, 2012; U.S. Provisional Patent Application No. 61/644,401 filed May 8,2012; U.S. Provisional Patent Application No. 61/644,397 filed May 8,2012; U.S. Provisional Patent Application No. 61/659,921 filed Jun. 14,2012; 61/680,641 filed Aug. 7, 2012 and U.S. Provisional PatentApplication No. 61/717,615 filed Oct. 23, 2012, the disclosures of eachof which are incorporated herein by reference in their entirety for allpurposes.

FIELD OF THE INVENTION

This application pertains generally to methods of treating oculardiseases, particularly those with elevated intraocular hypertension.

BACKGROUND OF THE INVENTION

Glaucoma is a collection of disorders characterized by progressivevisual field loss due to optic nerve damage. It is the leading cause ofblindness in the United States, affecting 1-2% of individuals aged 60and over. Although there are many risk factors associated with thedevelopment of glaucoma (age, race, myopia, family history, and injury),elevated intraocular pressure (IOP), also known as ocular hypertension(OH), is the only risk factor successfully manipulated and correlatedwith the reduction of glaucomatous optic neuropathy. Public healthfigures estimate that 2.5 million Americans manifest ocularhypertension.

In glaucoma associated with an elevation in eye pressure the source ofresistance to outflow is in the trabecular meshwork. The tissue of thetrabecular meshwork allows the “aqueous” to enter Schlemm's canal, whichthen empties into aqueous collector channels in the posterior wall ofSchlemm's canal and then into aqueous veins. The aqueous or aqueoushumor is a transparent liquid that fills the region between the corneaat the front of the eye and the lens. The aqueous humor is constantlysecreted by the ciliary body around the lens, so there is a continuousflow of the aqueous humor from the ciliary body to the eye's frontchamber. The eye's pressure is determined by a balance between theproduction of aqueous and its exit through the trabecular meshwork(major route) or via uveal scleral outflow (minor route). The trabecularmeshwork is located between the outer rim of the iris and the internalperiphery of the cornea. The portion of the trabecular meshwork adjacentto Schlemm's canal causes most of the resistance to aqueous outflow(juxtacanalicular meshwork).

Glaucoma is grossly classified into two categories: closed-angleglaucoma and open-angle glaucoma. Closed-angle glaucoma is caused byclosure of the anterior angle by contact between the iris and the innersurface of the trabecular meshwork. Closure of this anatomical angleprevents normal drainage of aqueous humor from the anterior chamber ofthe eye. Open-angle glaucoma (OAG) is any glaucoma in which the angle ofthe anterior chamber remains open, but the exit of aqueous through thetrabecular meshwork is diminished. The exact cause for diminishedfiltration is unknown for most cases of open-angle glaucoma. However,there are secondary open-angle glaucomas that may include edema orswelling of the trabecular spaces (from steroid use), abnormal pigmentdispersion, or diseases such as hyperthyroidism that produce vascularcongestion.

Although there is no known cure, the principal objective in treatingpatients with OAG or OH is to preserve visual function by the reductionand maintenance of IOP. As such all current therapies for glaucoma aredirected at decreasing intraocular pressure. Self-administered topicalagents or pills are usually the first-line choice of therapy forreducing IOP. This therapy reduces the production of aqueous humor orincreases the outflow of aqueous. Other means to treat glaucoma andocular hypertension, involve surgical therapy for open-angle glaucomasuch as laser (trabeculoplasty), trabeculectomy and aqueous shuntingimplants after failure of trabeculectomy or if trabeculectomy isunlikely to succeed. Trabeculectomy is a major surgery that is mostwidely used and is augmented with topically applied anticancer drugssuch as 5-flurouracil or mitomycin-c to decrease scarring and increasesurgical success.

Topical eye drops, though effective, can be inefficient. For instance,when an eye drop is instilled in an eye, it often overfills theconjunctival sac (i.e., the pocket between the eye and the lids) causinga substantial portion of the drop to be lost due to overflow of the lidmargin and spillage onto the cheek. In addition, a large portion of thedrop remaining on the ocular surface can be washed away into and througha lacrimal canaliculus, thereby diluting the concentration of the drugbefore it can treat the eye. Further, in many cases, topically appliedmedications have a peak ocular effect within about two hours, afterwhich additional applications of the medications should be performed tomaintain the therapeutic benefit. PCT Publication WO 06/014434 (Lazar),which is incorporated herein by reference in its entirety, may berelevant to these or other issues associated with eye drops.

Compounding ocular management difficulty, patients often do not usetheir eye drops as prescribed. Noncompliance rates of at least 25% arereported. This poor compliance can be due to discomfort and the normalreflex to protect the eye. Therefore, one or more drops may miss theeye. Older patients may have additional problems instilling drops due toarthritis, unsteadiness, and decreased vision. Pediatric and psychiatricpopulations pose difficulties as well.

Prostaglandins are one group of drugs administered as eye drops topatients diagnosed with glaucoma. Latanoprost is an ester analogue ofprostaglandin F_(2α) that reduces IOP by increasing uveoscleral outflow.Latanoprost is marketed as Xalatan® (latanoprost ophthalmic solution)0.005% (50 μg/mL) (Xalatan PI 2011). The IOP-lowering efficacy ofXalatan lasts for up to 24 hours after a single topical dose, whichallows for a once daily dosage regimen.

Lacrimal implants are devices that are inserted into a punctum and anassociated lacrimal canaliculus of an eye, either to block drainage oftears (to prevent conditions such as dry eye), or to contain a quantityof drug for release into the eye.

FIGS. 1-2 illustrate example views of anatomical tissue structuresassociated with an eye 100. Certain of the anatomical tissue structuresshown may be suitable for treatment using the various lacrimal implantsand methods discussed herein. The eye 100 is a spherical structureincluding a wall having three layers: an outer sclera 102, a middlechoroid layer 104 and an inner retina 106. The sclera 102 includes atough fibrous coating that protects the inner layers. It is mostly whiteexcept for the transparent area at the front, commonly known as thecornea 108, which allows light to enter the eye 100.

The choroid layer 104, situated inside the sclera 102, contains manyblood vessels and is modified at the front of the eye 100 as a pigmentediris 110. A biconvex lens 112 is situated just behind the pupil. Achamber 114 behind the lens 112 is filled with vitreous humor, agelatinous substance. Anterior and posterior chambers 116 are situatedbetween the cornea 108 and iris 110, respectively and filled withaqueous humor. At the back of the eye 100 is the light-detecting retina106.

The cornea 108 is an optically transparent tissue that conveys images tothe back of the eye 100. It includes a vascular tissue to whichnutrients and oxygen are supplied via bathing with lacrimal fluid andaqueous humor as well as from blood vessels that line the junctionbetween the cornea 108 and sclera 102. The cornea 108 includes a pathwayfor the permeation of drugs into the eye 100.

Turning to FIG. 2, other anatomical tissue structures associated withthe eye 100 including the lacrimal drainage system, which includes asecretory system 230, a distributive system and an excretory system, areshown. The secretory system 230 comprises secretors that are stimulatedby blinking and temperature change due to tear evaporation and reflexsecretors that have an efferent parasympathetic nerve supply and secretetears in response to physical or emotional stimulation. The distributivesystem includes the eyelids 202 and the tear meniscus around the lidedges of an open eye, which spread tears over the ocular surface byblinking, thus reducing dry areas from developing.

The excretory system of the lacrimal drainage system includes, in orderof flow, drainage, the lacrimal puncta, the lacrimal canaliculi, thelacrimal sac 204 and the lacrimal duct 206. From the lacrimal duct 206,tears and other flowable materials drain into a passage of thenasolacrimal system. The lacrimal canaliculi include an upper (superior)lacrimal canaliculus 208 and a lower (inferior) lacrimal canaliculus210, which respectively terminate in an upper 212 and lower 214 lacrimalpunctum. The upper 212 and lower 214 punctum are slightly elevated atthe medial end of a lid margin at the junction 216 of the ciliary andlacrimal portions near a conjunctival sac 218. The upper 212 and lower214 punctum are generally round or slightly ovoid openings surrounded bya connective ring of tissue. Each of puncta 212, 214 leads into avertical portion 220, 222 of their respective canaliculus before turningmore horizontal at a canaliculus curvature 250 to join one another atthe entrance of the lacrimal sac 204. The canaliculi 208, 210 aregenerally tubular in shape and lined by stratified squamous epitheliumsurrounded by elastic tissue, which permits them to be dilated. Asshown, a lacrimal canaliculus ampulla 252 exists near an outer edge ofeach canaliculus curvature 250.

For numerous reasons (e.g., the size, shape, positioning, and materialsof some conventional lacrimal implants, and variability in punctum sizeand shape), retention of the implants in the punctum and associatedlacrimal canaliculus has been inconsistent. Users of lacrimal implantsmay inadvertently dislodge the lacrimal implant by wiping their eye.Further, some configurations of lacrimal implants may dislodgethemselves, such as when a user sneezes, or tears excessively.

Accordingly, it is desirable to have a lacrimal implant that solvesthese problems and provides improved retention across different sizes ofpuncta, while providing efficient administration of a therapeutic agentfor treatment of open angle glaucoma (OAG) and/or ocular hypertension(OH).

SUMMARY OF THE INVENTION

In an exemplary embodiment, the present invention provides methods ofreducing intraocular pressure (IOP) in an eye. In an exemplaryembodiment, the method of the invention utilizes a latanoprost-elutinglacrimal implant inserted into at least the upper punctum of an eye.Previous methods of delivering latanoprost to the eye using alatanoprost-eluting lacrimal implant have met with varied and minimalsuccess. For example, as show in FIG. 16, in an eye implanted with asingle latanoprost-eluting plug in the lower punctum, the reduction inIOP is minimal, and is substantially identical across a range oflatanoprost loadings: from 3.5 μg to 95 μg, the IOP does not decreaseeven though more latanoprost is being delivered by the plugs with higherlatanoprost loading. See, FIG. 17. Thus, it is surprising that themethods of the present invention, in which an eye has alatanoprost-eluting punctal implant in at least the upper punctum yieldsa statistically significant reduction in IOP after about two weeks.

In an exemplary embodiment, the methods of the invention provide areduction in IOP of at least about 4 mm Hg, at least about 5 mm Hg, atleast about 6 mm Hg or at least about 7 mm Hg from baseline during thetreatment period during which the lacrimal implant is inserted into atleast the upper punctum,

In various embodiments, the method of the invention includes implantinga first lacrimal implant through a first lacrimal punctum and into afirst lacrimal canaliculus of the eye of the patient. The first lacrimalimplant is configured to release an intraocular pressure-reducingtherapeutic agent to the eye of the patient on a sustained basis. In anexemplary embodiment, the first implant contains approximately 0 μg(blank), 46 μg or 95 μg of latanoprost and a second implant containsabout 95 μg of latanoprost or is a “blank” implant and does not compriselatanoprost. In an exemplary embodiment, the first implant is installedin the upper punctum and the second implant is installed in the lowerpunctum. In various embodiments, the location of the implants isreversed. In other embodiments, only the first lacrimal implant isinstalled in the upper punctum and no implant is placed in the lowerpunctum.

In certain embodiments, the method of the invention can includeimplanting more than one implant in more than one punctum of one or moreeye. Thus, in various embodiments, the method also includes implanting asecond lacrimal implant through a second punctum and into a secondlacrimal canaliculus of the eye of the patient, the second lacrimalimplant being configured to release the intraocular pressure-reducingtherapeutic agent to the eye of the patent on a sustained basis. In analternative embodiment, the second lacrimal implant is a blank.

In various embodiments, the implant is configured to release, on asustained basis over a selected time course to the eye, a total amountof the intraocular pressure-reducing therapeutic agent from acombination of the first lacrimal implant and the second lacrimalimplant greater than or equal to a recommended daily total dose of theintraocular pressure-reducing therapeutic agent in eye drop form toreduce intraocular pressure of the eye by at least 4 mm Hg from baselinefor a continuous period of time of at least 4 weeks after implantationof the first lacrimal implant and the second lacrimal implant.

In an exemplary embodiment, the invention provides a method for reducingintraocular pressure in an eye of a subject in need thereof. Anexemplary method includes implanting a first lacrimal implant through afirst punctum and into a first lacrimal canaliculus of an eye of thesubject. The first lacrimal implant is configured to release atherapeutically effective amount of an intraocular pressure-reducingtherapeutic agent to the eye of the patient on a sustained basis. Invarious embodiments a second implant is installed in a second punctum orin a second eye. Thus, there is provided a method as set forth above,further comprising implanting a second lacrimal implant through a secondpunctum and into a second lacrimal canaliculus of the eye of thesubject. The second lacrimal implant is configured to release theintraocular pressure-reducing therapeutic agent to the eye of the patenton a sustained basis. The method also includes, once the one or moreimplant is installed in an eye, releasing, on a sustained basis over aselected time course to the eye, a total amount of the intraocularpressure-reducing therapeutic agent from a combination of the firstlacrimal implant and the second lacrimal implant. The total amount oftherapeutic agent released is sufficient to reduce the intraocularpressure.

The implant can be of any useful form, structure or composition. In anexemplary embodiment, the implant includes, a first member defining afirst axis and having a first end along the first axis. The implant alsoincludes a second member defining a second axis and having a second endalong the second axis; and a third member connecting the first end ofthe first member and the second end of the second member at a firstangle to form an angled intersection, and the third member comprising abore that is characterized by a third axis and a second angle. Ingeneral, the first angle is defined by the first axis with respect tothe second axis, the second angle is defined by the first axis withrespective to the third axis, and the bore is configured to beaccessible to an insertion tool for facilitating insertion of theimplant.

Also provided are kits that include at least one implant. An exemplarykit includes one or more implant operatively engaged to an implantingtool of use in implanting the device in the punctum of a subject's eye.

The devices and methods described herein include a removable, andoptionally drug releasing, lacrimal implant, which can be implanted inthe lacrimal canaliculus through a lacrimal punctum. In variousembodiments, the lacrimal implants described herein utilize the featuresof the nasolacrimal drainage system (e.g., by mimicking the shape of thelacrimal canaliculus) to provide improved patient comfort and implantretention in the ocular anatomy. In this way, exemplary lacrimalimplants described herein overcome drawbacks associated with currentimplants. The lacrimal implants described herein are easily implantedand removed without much biasing of the lacrimal punctum or associatedcanaliculus, and are securely retained in the lacrimal canaliculus uponimplantation, optionally without being pre-sized to a particularlacrimal punctum or canaliculus diameter. In various embodiments, theimplants are drug delivery system, providing sustained, localizedrelease of one or more drugs or other therapeutic agents at a desiredtherapeutic level for an extended period of time.

In an exemplary embodiment, the invention provides an implant forinsertion into a lacrimal canaliculus. An exemplary implant includes, afirst member defining a first axis and having a first end along thefirst axis. The implant also includes a second member defining a secondaxis and having a second end along the second axis. The implant furtherincludes a third member connecting the first end of the first member andthe second end of the second member at a first angle to form an angledintersection. The third member includes a bore that is characterized bya third axis and a second angle. The bore is configured to be accessibleto an insertion tool for facilitating insertion of the implant. Invarious embodiments, the first angle is defined by the first axis withrespect to the second axis and the second angle is defined by the firstaxis with respective to the third axis.

In various embodiments, the invention includes a kit having an implantof the invention and an insertion tool for inserting the implant intothe punctum.

Also provided is a method of treating an ocular disease using one ormore punctal implant.

These and other embodiments, advantages, and aspects of the methodsdisclosed herein are set forth in part in following detaileddescription.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, like numerals describe similar components throughoutthe several views. Like numerals having different letter suffixesrepresent different instances of similar components. The drawingsillustrate generally, by way of example, but not by way of limitation,various embodiments disclosed herein.

FIG. 1 illustrates an example of anatomical tissue structures associatedwith an eye, certain of these tissue structures providing a suitableenvironment in which a lacrimal implant can be used.

FIG. 2 illustrates another example of anatomical tissue structuresassociated with an eye, certain of these tissue structures providing asuitable environment in which a lacrimal implant can be used.

FIG. 3A provides a perspective view of an implant in accordance with anembodiment of the present invention.

FIG. 3B is a side view of an implant in accordance with an embodiment ofthe present invention.

FIG. 3C is a side view illustrating the second member and the thirdmember of an implant in accordance with an embodiment of the presentinvention.

FIG. 3D is a back view of an implant in accordance with an embodiment ofthe present invention.

FIG. 3E is a cross-sectional view taken about line III(E)-III(E) of FIG.3D depicting an implant with a bore, in accordance with an embodiment ofthe present invention.

FIG. 3F is a partially enlarged view of FIG. 3E taken about circleIII(F) depicting the second member, the third member and a bore formedin the third member of an implant, in accordance with an embodiment ofthe present invention.

FIG. 4A provides a perspective view of an implant in accordance with anembodiment of the present invention.

FIG. 4B is a cross-sectional view depicting an implant having a cavityformed in the second member, in accordance with an embodiment of thepresent invention.

FIG. 4C is a partially enlarged view taken about circle IV(C) of FIG. 4Bdepicting a cavity in the second member and a bore in the third memberof an implant, in accordance with an embodiment of the presentinvention.

FIG. 5 provides a partial cross-sectional view of an implant inaccordance with one embodiment of the present invention.

FIG. 6 provides a partial cross-section view of an implant in accordancewith another embodiment of the present invention.

FIG. 7 depicts engagement of an insertion tool with an implant inaccordance with an embodiment of the present invention.

FIG. 8A provides initial retention data for various exemplary implantsin accordance with various embodiments of the present invention.

FIG. 8B lists retention data for various exemplary implants over oneday, in accordance with various embodiments of the present invention.

FIG. 8C lists retention data for various exemplary implants over oneweek, in accordance with various embodiments of the present invention.

FIG. 8D lists retention data for various exemplary implants over twoweeks, in accordance with various embodiments of the present invention.

FIG. 8E lists retention data for various exemplary implants over fourweeks, in accordance with various embodiments of the present invention.

FIG. 8F lists retention data for various exemplary implants over eightweeks, in accordance with various embodiments of the present invention.

FIG. 8G lists retention data for various exemplary implants over twelveweeks, in accordance with various embodiments of the present invention.

FIG. 9 is a plot comparing retention rates of an implant of theinvention (lower punctum) with a commercial implant (upper punctum). Thetwo implants are implanted in the same eye of the patient.

FIG. 10A illustrates a side view of a commercial implant used for thecomparison studies herein.

FIG. 10B illustrates a top view of the commercial implant used for thecomparison studies herein.

FIG. 10C is a cross-sectional view taken about line A-A of FIG. 10Aillustrating a modified cavity formed in the commercial implant for thecomparison studies herein.

FIG. 10D is a partially enlarged view taken about circle B of FIG. 10Cillustrating a lip at an opening of the modified cavity in thecommercial implant for the comparison studies herein.

FIG. 11 provides the baseline demographics for the comparison studiesherein.

FIG. 12 lists retention data for various exemplary implants over fourweeks, in accordance with various embodiments of the present invention.

FIG. 13 illustrates mean intraocular pressure (IOP) change from baselineduring treatment with a sustained release ophthalmic drug deliverysystem according to an embodiment of the present invention over afour-week period.

FIG. 14 illustrates percentage of subjects achieving categoricalabsolute intraocular pressure (IOP) reduction from baseline duringtreatment with the sustained release ophthalmic drug delivery systemaccording to an embodiment of the present invention over the four-weekperiod.

FIG. 15 illustrates percent change in IOP from baseline during treatmentwith a sustained release ophthalmic drug delivery system according to anembodiment of the present invention over a four-week period.

FIG. 16 illustrates the lack of dose dependency of intraocular pressurereduction when latanoprost is administered from a single punctalimplant.

FIG. 17 illustrates the dosages of latanoprost delivered by the punctalimplants of FIG. 16.

FIG. 18 is a graphical illustration comparing change in IOP frombaseline during treatment in the GLAU 11 and GLAU 12 Studies with asustained release opthalmic drug delivery system according to anembodiment of the present invention. The data marked (▪) are for apunctal plug with an unoptimized drug core. 141 μg, the maximum dosage,is administered by upper (46 μg) and lower (95 μg) plugs. The datamarked (♦) are for a punctal plug modified to enhance insertion andretention. The maximum dosage, 141 μg, is administered by upper (46 μg)and lower (95 μg) plugs. The results show a comparable, in two studies,sustained reduction in IOP at week 4 of more than 5 mmHg. N=number ofeyes.

FIG. 19 is a graphical illustration comparing change in IOP frombaseline during treatment with a sustained release ophthalmic drugdelivery system according to an embodiment of the present invention. Thedata marked (♦) are for a punctal plug modified to enhance insertion andretention. The maximum dosage, 95 μg, is administered by an upper (95μg) plug. The lower plug is a blank. The data marked (▪) are for apunctal plug modified to enhance insertion and retention. The maximumdosage, 95 μg, is administered by an upper (95 μg) plug. The lower plugis open. The data marked (▴) are for a punctal plug modified to enhanceinsertion and retention. The maximum dosage, 95 μg, is administered bylower (95 μg) plug. The upper plug is a blank

FIG. 20 is a graphical illustration comparing change in IOP frombaseline during treatment with a sustained release ophthalmic drugdelivery system according to an embodiment of the present invention. Thedata marked (♦) are for a punctal plug modified to enhance insertion andretention. The maximum dosage administered is 95 μg. The data marked (▪)are for a punctal plug modified to enhance insertion and retention. Themaximum dosage adminstered is 141 μg. The data marked (▴) are for apunctal plug modified to enhance insertion and retention. The maximumdosage administered is 190 μg.

FIG. 21 is a graphical illustration of the five treatment arms of GLAU12 and GLAU 13 (Ex. 5 and 6). N=number of subjects

FIG. 22 is a graphical illustration of the two treatment arms for GLAU12 Addendum exploring the effect of repeat plug placement. N=number ofsubjects

FIG. 23 lists a summary of change in IOP from baseline (mmHg) in theGLAU 12 and GLAU 13 studies for both intent to treat (ITT) groups.N=number of eyes

FIG. 24 is a graphical illustration of the reduction in IOP (mmHg) forthe All IOP ITT group of the GLAU 12 study from day 1 to week 12.N=number of eyes.

FIG. 25 is a graphical illustration of the reduction in IOP (mmHg) forthe second ITT group (IOP excluded after first plug loss/removal) of theGLAU 12 study from day 1 to week 12. N=number of eyes.

FIG. 26 is a graphical illustration of the reduction in IOP (mmHg) forboth ITT groups in the GLAU 12 addendum study during course 2 (anadditional 8 weeks after the 12 week main study). N=number of eyes.

FIG. 27 is a graphical illustration of the reduction in IOP (mmHg) forthe All IOP ITT group of the GLAU 13 study from day 1 to week 12. Thedata indicates that the effect of latanoprost and the reduction in IOPmay be influenced by the plug position. N=number of eyes.

FIG. 28 is a graphical illustration of the reduction in IOP (mmHg) forthe second ITT group (IOP excluded after first plug loss/removal) of theGLAU 13 study from day 1 to week 12. The data indicates that the effectof latanoprost and the reduction in IOP may be influenced by the plugposition. N=number of eyes.

FIG. 29 is a graphical illustration of the change in IOP (mmHg) frombaseline over 12 weeks showings the percentage of eyes with a betterthan 5 mmHg decrease in IOP for the All IOP ITT group of GLAU 12.N=number of eyes.

FIG. 30 is a graphical illustration of the change in IOP (mmHg) frombaseline over 12 weeks showings the percentage of eyes with a betterthan 5 mmHg decrease in IOP for the second ITT group (IOP excluded afterfirst plug loss/removal) of GLAU 12. N=number of eyes.

FIG. 31 is a graphical illustration of the change in IOP (mmHg) frombaseline over 12 weeks showings the percentage of eyes with a betterthan 5 mmHg decrease in IOP for the All IOP ITT group of GLAU 13.N=number of eyes.

FIG. 32 is a graphical illustration of the change in IOP (mmHg) frombaseline over 12 weeks showings the percentage of eyes with a betterthan 5 mmHg decrease in IOP for the second ITT group (IOP excluded afterfirst plug loss/removal) of GLAU 13. N=number of eyes.

FIG. 33 is a list and description of the plug designs used in the GLAU11, 12 and 13 studies.

FIG. 34 is a graphical illustration of the upper and lower plugretention by eye represented as a percentage at each time point from day1 to week 12 for the plugs used in the GLAU 12 study.

FIG. 35 is a table listing the upper and lower plug retention by eyerepresented as a percentage at each time point from day 1 to week 12 forthe plugs used in the GLAU 12 study. N=number of eyes.

FIG. 36 is a graphical illustration of the upper and lower plugretention by eye represented as a percentage at each time point forCourse 2 (8 weeks) and Course 3 (4 weeks) for the plugs used in the GLAU12 addendum study.

FIG. 37 is a graphical illustration of the upper and lower plugretention by eye represented as a percentage at each time point from day1 to week 12 for the plugs used in the GLAU 13 study.

FIG. 38 is a table listing the upper and lower plug retention by eyerepresented as a percentage at each time point from day 1 to week 12 forthe plugs used in the GLAU 13 study. N=number of eyes.

FIG. 39 is a table representing the upper plug retention by eyerepresented as a percentage in 4 week blocks (0-4 weeks, 4-8 weeks and8-12 weeks) for the plugs used in the GLAU 12 and GLAU 13 studies

DETAILED DESCRIPTION OF THE INVENTION A) Introduction

In various embodiments, the present invention is directed to thetreatment of ocular diseases such as Glaucoma or ocular hypertension. Incertain embodiments, the invention includes the use of an implant thatcomprises a sustained release formulation of a therapeutic agent of usein treating the disease. The implant is configured to deliver atherapeutically effective amount of the therapeutic agent to the eyeduring the period that it is implanted in the eye (e.g. the treatmentperiod). In an exemplary embodiment, the disease is glaucoma and thetherapeutic agent is a prostaglandin or derivative thereof. In certainembodiments, the implant is a punctual plug configured for insertionthrough a human lacrimal punctum into a corresponding lacrimalcanaliculus and retention in the canaliculus. In an exemplaryembodiment, the sustained release formulation of the therapeutic agentis released over a period of from about 4 weeks to about 12 weeks in atherapeutic dose sufficient to reduce intraocular pressure of the eye.In various embodiments, the therapeutic dose of the agent is sufficientto decrease intraocular pressure by at least 4 mm Hg from baseline(e.g., “normal”).

In certain embodiments is provided a method for treating a patientdiagnosed with Open Angle Glaucoma (OAG) or Ocular Hypertension (OH) inan eye. In this instance lacrimal implants are provided for insertioninto the upper and/or lower punctum of the eye. Each lacrimal implantcomprises a sustained release formulation of a therapeutic agent fortreating OAG and/or OH, wherein the sustained release formulation can bereleased in a therapeutically effective amount for at least 4 weeks andup to 12 weeks or longer. In one embodiment, the lacrimal implant isinserted at least in the upper punctum. In one aspect thistherapeutically effective agent is latanoprost. In this instance oftreating OAG and/or OH the IOP is reduced. In an exemplary embodiment,the methods of the invention provide a reduction in IOP of at leastabout 4 mm Hg, at least about 5 mm Hg, at least about 6 mm Hg or atleast about 7 mm Hg from baseline during the treatment period.

In certain embodiments, a method for treating a patient diagnosed withOpen Angle Glaucoma (OAG) or Ocular Hypertension (OH) in an eye isprovided wherein a first lacrimal implant comprising a sustained releaseformulation of the therapeutic agent is inserted into a upper or lowerpunctum and a second lacrimal implant that does not comprise thetherapeutic agent is inserted into the open punctum of the eye (i.e. theupper or lower punctum that does not contain the first lacrimalimplant). The second lacrimal implant is also referred to herein as a“blank” implant. In one embodiment the therapeutic agent is released ina therapeutically effective dose from the first lacrimal implant on asustained release basis over at least four (4) weeks. In another aspect,the therapeutic agent is released in a therapeutically effective dosefrom the first lacrimal implant on a sustained release basis over atleast twelve (12) weeks.

In certain other embodiments, a method for treating a patient diagnosedwith Open Angle Glaucoma (OAG) or Ocular Hypertension (OH) in an eye isprovided wherein the IOP of the eye is measured to obtain a baseline IOPbefore treatment and wherein a lacrimal implant comprising a sustainedrelease formulation is inserted into a punctum. In exemplary embodimentsthe IOP is reduced by at least 5.5 mm Hg from baseline at week 6,reduced by at least 4.0 mm Hg from baseline at week 12, or reduced by atleast 5.0 mm Hg from baseline at week 12.

In an exemplary embodiment, the method of the invention utilizeslatanoprost-eluting punctal implants. Previous methods of deliveringlatanoprost to the eye using a latanoprost-eluting punctal implant havemet with varied and minimal success. For example, as show in FIG. 16, inan eye implanted with a single latanoprost-eluting plug in the lowerpunctum, the reduction in IOP is minimal, and is substantially identicalacross a range of latanoprost loadings: from 3.5 μg to 95 μg, the IOPdoes not decrease even though more latanoprost is being delivered by theplugs with higher latanoprost loading. See, FIG. 17. Thus, it issurprising that the methods of the present invention, in which either aneye has a latanoprost-eluting punctal implant in both the upper andlower punctum, a blank and latanoprost-eluting punctual implant ineither the upper and lower punctum, or in certain instances alatanoprost-eluting punctal implant in the upper punctum and no implantin the bottom punctum, would yield a statistically significant reductionin IOP after about two weeks. See Example 6 and Table 8

Also disclosed herein are exemplary structures of ocular implants of usein the methods of the invention for treating various diseases anddisorders. Exemplary structures include lacrimal implants for at leastpartial insertion through the lacrimal punctum and into its associatedcanaliculus. Various embodiments further provide an insertion tool forplacing a lacrimal implant into a lacrimal punctum. Also disclosedherein are exemplary implants including therapeutic agents incorporatedthroughout the device, within one or more section of the device, or in atherapeutic agent core, e.g., a localized therapeutic agent core. Thedevices of the invention are of use for treating various diseases.

In the various embodiments of methods of the invention, implanting alacrimal implant of the invention through the lacrimal punctum and intoits associated canaliculus, in various embodiments, inhibits or blockstear flow therethrough. In various embodiments, a device inhibiting orblocking tear flow is of use to treat dry eye. In an exemplaryembodiment, the insertion of the lacrimal implant allows for thedelivery of a therapeutic agent. In various embodiments, the delivery issustained delivery. Exemplary therapeutic agents incorporated into theimplants of the invention are of use to treat the eye, or they can be ofuse more broadly systemic therapies. For example, using a device of theinvention, the therapeutic agent can be delivered to a nasal passage, toan inner ear system, or to other passages or systems for treatment ofvarious diseases including, but not limited to, eye infection, eyeinflammation, glaucoma, other ocular disease, other ocular disorder, asinus or allergy disorder, dizziness or a migraine. The devices of theinvention are of use for systemic delivery of one or more therapeuticagents in an amount having therapeutic efficacy.

Those of ordinary skill in the art will understand that the followingdetailed description of the present invention is illustrative only andis not intended to be in any way limiting. Other embodiments of thepresent invention will readily suggest themselves to such skilledpersons having benefit of this disclosure. Reference will now be made indetail to implementations of the present invention as illustrated in theaccompanying drawings. The same reference indicators will be usedthroughout the drawings and the following detailed description to referto the same or like parts.

B) Definitions

As used herein, the terms “a” or “an” are used, as is common in patentdocuments, to include one or more than one, independent of any otherinstances or usages of “at least one” or “one or more.”

As used herein, the term “or” is used to refer to a nonexclusive or,such that “A or B” includes “A but not B,” “B but not A,” and “A and B,”unless otherwise indicated.

As used herein, the term “about” is used to refer to an amount that isapproximately, nearly, almost, or in the vicinity of being equal to oris equal to a stated amount, e.g., the state amount plus/minus about 5%,about 4%, about 3%, about 2% or about 1%.

As used herein, an “axis” refers to a general direction along which amember extends. According to this definition, the member is not requiredto be entirely or partially symmetric with respect to the axis or to bestraight along the direction of the axis. Thus, in the context of thisdefinition, any member disclosed in the present applicationcharacterized by an axis is not limited to a symmetric or a straightstructure.

In this document, the term “proximal” refers to a location relativelycloser to the cornea of an eye, and the term “distal” refers to alocation relatively further from the cornea and inserted deeper into alacrimal canaliculus.

In the appended claims, the terms “including” and “in which” are used asthe plain-English equivalents of the respective terms “comprising” and“wherein.” Also, in the following claims, the terms “including” and“comprising” are open-ended, that is, a system, assembly, device,article, or process that includes elements in addition to those listedafter such a term in a claim are still deemed to fall within the scopeof that claim. Moreover, in the following claims, the terms “first,”“second,” and “third,” etc. are used merely as labels, and are notintended to impose numerical requirements on their objects.

As used herein, the term “adverse event” refers to any undesirableclinical event experienced by a patient undergoing a therapeutictreatment including a drug and/or a medical device, whether in aclinical trial or a clinical practice. Adverse events include a changein the patient's condition or laboratory results, which has or couldhave a deleterious effect on the patient's health or well-being. Forexample, adverse events include but are not limited to: devicemalfunction identified prior to placement, device malposition, devicemalfunction after placement, persistent inflammation, endophthalmitis,corneal complications (corneal edema, opacification, or graftdecompensation), chronic pain, iris pigmentation changes, conjunctivalhyperemia, eyelash growth (increased length, thickness, pigmentation,and number of lashes), eyelid skin darkening, intraocular inflammation(iritis/uveitis), macular edema including cystoid macular edema, blurredvision, burning and stinging, foreign body sensation, itching, punctateepithelial keratopathy, dry eye, excessive tearing, eye pain, lidcrusting, lid discomfort/pain, lid edema, lid erythema, photophobia, VAdecrease, conjunctivitis, diplopia, discharge from the eye, retinalartery embolus, retinal detachment, vitreous hemorrhage from diabeticretinopathy, upper respiratory tract infection/cold/flu, chestpain/angina pectoris, muscle/joint/back pain, and rash/allergic skinreaction, eye pruritus, increase in lacrimation, ocular hyperemia andpunctate keratitis. In an exemplary embodiment, use of the device andmethod of the invention results in one or more of: (i) occurrence offewer adverse events; or (ii) adverse events of less severity, thanthose occurring with the use of a therapeutic agent in drop form, e.g.,when the therapeutic agent is administered via drops in essentially thesame unit dosage as that delivered by a device as set forth herein.

As used herein, the phrase “consisting essentially of” limits acomposition to the specified materials or steps and those additional,undefined components that do not materially affect the basic and novelcharacteristic(s) of the composition.

As used herein, the term “continuous” or “continuously” meansessentially unbroken or uninterrupted. For example, continuouslyadministered active agents are administered over a period of timeessentially without interruption.

As used herein, the term “diameter” encompasses a broad meaning. Forexample, with respect to a member having a circular cross section, theterm “diameter” has the conventional meaning and refers to a straightline through the center of the circle connecting two points on thecircumference. When the cross section is not a circle, the term“diameter” in the present disclosure refers to the characteristicdiameter of the cross section. The “characteristic diameter” refers tothe diameter of a circle that has the same surface area as the crosssection of the element. In the present application, “diameter” isinterchangeable with “characteristic diameter.”

As used herein, the term “eye” refers to any and all anatomical tissuesand structures associated with an eye. The eye is a spherical structurewith a wall having three layers: the outer sclera, the middle choroidlayer and the inner retina. The sclera includes a tough fibrous coatingthat protects the inner layers. It is mostly white except for thetransparent area at the front, the cornea, which allows light to enterthe eye. The choroid layer, situated inside the sclera, contains manyblood vessels and is modified at the front of the eye as the pigmentediris. The biconvex lens is situated just behind the pupil. The chamberbehind the lens is filled with vitreous humour, a gelatinous substance.The anterior and posterior chambers are situated between the cornea andiris, respectively and filled with aqueous humour. At the back of theeye is the light-detecting retina. The cornea is an opticallytransparent tissue that conveys images to the back of the eye. Itincludes avascular tissue to which nutrients and oxygen are supplied viabathing with lacrimal fluid and aqueous humour as well as from bloodvessels that line the junction between the cornea and sclera. The corneaincludes one pathway from the permeation of drugs into the eye. Otheranatomical tissue structures associated with the eye include thelacrimal drainage system, which includes a secretory system, adistributive system and an excretory system. The secretory systemcomprises secretors that are stimulated by blinking and temperaturechange due to tear evaporation and reflex secretors that have anefferent parasympathetic nerve supply and secrete tears in response tophysical or emotional stimulation. The distributive system includes theeyelids and the tear meniscus around the lid edges of an open eye, whichspread tears over the ocular surface by blinking, thus reducing dryareas from developing.

As used herein, the term “implant” refers to a structure that can beconfigured to contain or be impregnated with a drug, for example via adrug core or a drug matrix, such as those as disclosed in this patentdocument and in WO 07/115,261, which is herein incorporated by referencein its entirety, and which is capable of releasing a quantity of activeagent, such as latanoprost or other intraocular pressure-reducingtherapeutic agent(s), into tear fluid for a sustained release period oftime when the structure is implanted at a target location along the pathof the tear fluid in the patient. The terms “implant,” “plug,” “punctalplug,” and “punctal implant” are meant herein to refer to similarstructures. Likewise, the terms “implant body” and “plug body” are meantherein to refer to similar structures. The implants described herein maybe inserted into the punctum of a subject, or through the punctum intothe canaliculus. The implant may be also the drug core or drug matrixitself, which is configured for insertion into the punctum without beinghoused in a carrier such as a punctal implant occluder, for examplehaving a polymeric component and a latanoprost or other intraocularpressure-reducing therapeutic agent(s) component with no additionalstructure surrounding the polymeric component and latanoprost or otherintraocular pressure-reducing therapeutic agent(s) component.

As used in exemplary embodiments herein, “loss of efficacy” (LoE) isdefined as an IOP increase to baseline (post-washout) IOP in either orboth eyes while wearing a latanoprost punctal plug delivery system(L-PPDS) continuously from Day 0. Subjects were followed for at least 4weeks before the subject could complete the study due to LoE and LoE wasconfirmed at 2 sequential visits.

As used herein, a “pharmaceutically acceptable vehicle” is anyphysiologically acceptable vehicle known to those of ordinary skill inthe art useful in formulating pharmaceutical compositions. Suitablevehicles include polymeric matrices, sterile distilled or purifiedwater, isotonic solutions such as isotonic sodium chloride or boric acidsolutions, phosphate buffered saline (PBS), propylene glycol andbutylene glycol. Other suitable vehicular constituents includephenylmercuric nitrate, sodium sulfate, sodium sulfite, sodium phosphateand monosodium phosphate. Additional examples of other suitable vehicleingredients include alcohols, fats and oils, polymers, surfactants,fatty acids, silicone oils, humectants, moisturizers, viscositymodifiers, emulsifiers and stabilizers. The compositions may alsocontain auxiliary substances, i.e. antimicrobial agents such aschlorobutanol, parabans or organic mercurial compounds; pH adjustingagents such as sodium hydroxide, hydrochloric acid or sulfuric acid; andviscosity increasing agents such as methylcellulose. An exemplary finalcomposition is sterile, essentially free of foreign particles, and has apH that allows for patient comfort and acceptability balanced with a pHthat is desirable for optimum drug stability. An exemplary“pharmaceutically acceptable vehicle is an “ophthalmically acceptablevehicle” as used herein refers to any substance or combination ofsubstances which are non-reactive with the compounds and suitable foradministration to patient. In an exemplary embodiment, the vehicle is anaqueous vehicle suitable for topical application to the patient's eyes.In various embodiments, the vehicle further includes other ingredientswhich may be desirable to use in the ophthalmic compositions of thepresent invention include antimicrobials, preservatives, co-solvents,surfactants and viscosity building agents.

In various embodiments, the “pharmaceutically acceptable vehicle”includes more than one therapeutic agent.

As used herein, the term “punctum” refers to the orifice at the terminusof the lacrimal canaliculus, seen on the margins of the eyelids at thelateral extremity of the lacus lacrimalis. Puncta (plural of punctum)function to reabsorb tears produced by the lacrimal glands. Theexcretory part of the lacrimal drainage system includes, in flow orderof drainage, the lacrimal puncta, the lacrimal canaliculi, the lacrimalsac and the lacrimal duct. From the lacrimal duct, tears and otherflowable materials drain into a passage of the nasal system. Thelacrimal canaliculi include an upper (superior) lacrimal canaliculus anda lower (inferior) lacrimal canaliculus, which respectively terminate inan upper and lower lacrimal punctum. The upper and lower punctum areslightly elevated at the medial end of a lid margin at the junction ofthe ciliary and lacrimal portions near a conjunctival sac. The upper andlower punctum are generally round or slightly ovoid openings surroundedby a connective ring of tissue. Each of the puncta leads into a verticalportion of their respective canaliculus before turning more horizontalat a canaliculus curvature to join one another at the entrance of thelacrimal sac. The canaliculi are generally tubular in shape and lined bystratified squamous epithelium surrounded by elastic tissue, whichpermits them to be dilated.

The terms “subject” and “patient” refer to animals such as mammals,including, but not limited to, primates (e.g., humans), cows, sheep,goats, horses, dogs, cats, rabbits, rats, mice and the like. In manyembodiments, the subject or patient is a human.

An “intraocular pressure-reducing therapeutic agent” can comprise a drugand may be any of the following or their equivalents, derivatives oranalogs, including anti-glaucoma medications (e.g. adrenergic agonists,adrenergic antagonists (beta blockers), carbonic anhydrase inhibitors(CAIs, systemic and topical), therapeutic agent(s) such asprostaglandins, antiprostaglandins, prostaglandin precursors, includingantiglaucoma drugs including beta-blockers such as timolol, betaxolol,levobunolol, atenolol (see U.S. Pat. No. 4,952,581); adrenergic agonistsincluding clonidine derivatives, such as apraclonidine or brimonidine(see U.S. Pat. No. 5,811,443); and prostaglandin analogues such asbimatoprost, travoprost, tafluprost, latanoprost, etc. In an exemplaryembodiment, the therapeutic agent is already marketed for glaucoma, andcommercially available preparations thereof can be used. Furthertherapeutic agents include carbonic anhydrase inhibitors such asacetazolamide, dorzolamide, brinzolamide, methazolamide,dichlorphenamide, diamox; and the like.

The term “topical” refers to any surface of a body tissue or organ. Atopical formulation is one that is applied to a body surface, such as aneye, to treat that surface or organ. Topical formulations as used hereinalso include formulations that can release therapeutic agents into thetears to result in topical administration to the eye.

As used herein, the term “treating” or “treatment” of a state, disease,disorder, injury or condition as used herein is understood to mean oneor more of (1) preventing or delaying the appearance of clinicalsymptoms of the state, disease, disorder, injury or condition developingin a mammal that may be afflicted with or predisposed to the state,disease, disorder, injury or condition but does not yet experience ordisplay clinical or subclinical symptoms of the state, disease,disorder, injury or condition, (2) inhibiting the state, disease,disorder, injury or condition, i.e., arresting or reducing thedevelopment of the disease or at least one clinical or subclinicalsymptom thereof, or (3) relieving the state, disease, disorder, injuryor condition, i.e., causing regression of the state, disease, disorder,injury or condition or at least one of its clinical or subclinicalsymptoms. In an exemplary embodiment, the present invention provides amethod of treating glaucoma or ocular hypertension including contactingan effective intraocular pressure reducing amount of a composition withthe eye in order to reduce eye pressure and to maintain the pressure ona reduced level for a sustained period, e.g., at least about 1, 2, 3, 4,5, 6, 7 8, 9, 10, 11 or 12 weeks.

The term “delivering”, as used herein, shall be understood to meanproviding a therapeutically effective amount of a pharmaceuticallyactive agent to a particular location within a host causing atherapeutically effective concentration of the pharmaceutically activeagent at the particular location.

As used herein, the term “diameter” encompasses a broad meaning. Forexample, with respect to a member having a circular cross section, theterm “diameter” has the conventional meaning and refers to a straightline through the center of the circle connecting two points on thecircumference. When the cross section is not a circle, the term“diameter” in the present disclosure refers to the characteristicdiameter of the cross section. The “characteristic diameter” refers tothe diameter of a circle that has the same surface area as the crosssection of the element. In the present application, “diameter” isinterchangeable with “characteristic diameter.”

Some embodiments of the invention provide the use of latanoprost oranother active agent or agents for treatment of diabetic retinopathy,uveitis, intraocular inflammation, keratitis, dry eye, macular edemaincluding cystoid macular edema, infection, macular degeneration,blurred vision, herpetic conjunctivitis, blepharitis, retinal orchoroidal neovascularizaton, and other proliferative eye diseases. Insome embodiments, the invention provides the use of an anti-glaucomadrug for treatment of the above diseases. In certain embodiments, theuse of a prostaglandin or prostaglandin analogue for treatment of theabove diseases is provided.

“Prostaglandin derivatives”, as used herein refers to compounds havingthe basic prostaglandin structure of 20 carbon atoms and a 5-carbonring. Exemplary prostaglandin derivatives of use in the presentinvention are of the PGI₂, PGE₂ and PGF₂α types. The structure can beaugmented by incorporating or eliminating functional groups (e.g., HO,carbonyl, ether, ester, carboxylic acid, halide) or by adding carbonatom-based radicals (e.g., Me, Et, i-Pr, etc.). See for example, U.S.Pat. No. 7,910,767. In some embodiments, the prostaglandin derivative isa derivative of PGA, PGB, PGD, PGE and PGF, in which the omega chain hasbeen modified with the common feature of containing a ring structure.See, U.S. Pat. No. 5,296,504. The prostaglandin derivatives of use inthe invention are synthesized de novo or derived from modification ofnaturally occurring prostaglandins.

C) Drug Delivery System

Applicants herein disclose a method for treating open angle glaucoma(OAG) and/or ocular hypertension (OH) in an eye of a patient utilizing alacrimal implant comprising a sustained release formulation to deliverthe therapeutic agent to the eye. The treatment of these eye diseasesrelies on a drug delivery system for administering the therapeuticagent, wherein the therapeutic agent may be a known drug for reducingIOP or a newly developed drug. The drug delivery system comprises 1) thetherapeutic agent, 2) the lacrimal implant and 3) sustained releaseformulations while taking into account the specific disease beingtreated.

Applicants provide herein, for the first time, methods for treating OAGand/or OH wherein a therapeutically effective dose of the therapeuticagent (e.g. latanoprost) is administered from the present lacrimalimplants over the treatment period (e.g. 4-12 weeks) wherein the IOP isreduced over the treatment period by a clinically meaningful amount(e.g. about 5 mm Hg from baseline.) In this instance, no additionaltreatment, except for the therapeutic agent eluted from the implants,was needed to reduce IOP by a clinically meaningful amount.

For ease of understanding the invention, the drug delivery system andeach of the components will be described in detail followed by methodsand clinical applications for treating OAG and/or OH wherein intraocularpressure (IOP) is reduced.

1) Therapeutic Agents

Generally, pharmaceutically active agents or drugs useful in the methodsof the present invention can be any compound, composition of matter, ormixtures thereof that can be delivered from an implant, such as thosedescribed herein, to produce a beneficial and useful result to, forexample, the eye, especially an agent effective in obtaining a desiredlocal or systemic physiological or pharmacological effect.

Examples of such agents include, but are not limited to, anesthetics andpain killing agents such as lidocaine and related compounds,benzodiazepam and related compounds and the like; anti-cancer agentssuch as 5-fluorouracil, adriamycin and related compounds and the like;anti-fungal agents such as fluconazole and related compounds and thelike; anti-viral agents such as trisodium phosphomonoformate,trifluorothymidine, acyclovir, ganciclovir, DDI, AZT and the like; celltransport/mobility impending agents such as colchicine, vincristine,cytochalasin B and related compounds and the like; antiglaucoma drugs(e.g. adrenergic agonists, adrenergic antagonists (beta blockers),carbonic anhydrase inhibitors (CAIs, systemic and topical),parasympathomimetics, prostaglandins and hypotensive lipids, andcombinations thereof), antimicrobial agent (e.g., antibiotic, antiviral,antiparacytic, antifungal, etc.), a corticosteroid or otheranti-inflammatory (e.g., an NSAID or other analgesic and pain managementcompounds), a decongestant (e.g., vasoconstrictor), an agent thatprevents of modifies an allergic response (e.g., an antihistamine,cytokine inhibitor, leucotriene inhibitor, IgE inhibitor,immunomodulator), a mast cell stabilizer, cycloplegic, mydriatic or thelike.

Other agents that can be incorporated into implants of use in theinvention include antihypertensives; decongestants such asphenylephrine, naphazoline, tetrahydrazoline and the like; immunologicalresponse modifiers such as muramyl dipeptide and related compounds andthe like; peptides and proteins such as cyclosporin, insulin, growthhormones, insulin related growth factor, heat shock proteins and relatedcompounds and the like; steroidal compounds such as dexamethasone,prednisolone and related compounds and the like; low solubility steroidssuch as fluocinolone acetonide and related compounds and the like;carbonic anhydrase inhibitors; diagnostic agents; antiapoptosis agents;gene therapy agents; sequestering agents; reductants such as glutathioneand the like; antipermeability agents; antisense compounds;antiproliferative agents; antibody conjugates; antidepressants; bloodflow enhancers; antiasthmatic drugs; antiparasiticagents; non-steroidalanti inflammatory agents such as ibuprofen and the like; nutrients andvitamins: enzyme inhibitors: antioxidants; anticataract drugs; aldosereductase inhibitors; cytoprotectants; cytokines, cytokine inhibitors,and cytokin protectants; uv blockers; mast cell stabilizers; antineovascular agents such as antiangiogenic agents, e.g., matrixmetalloprotease inhibitors and the like.

Representative examples of additional pharmaceutically active agent foruse herein include, but are not limited to, neuroprotectants such asnimodipine and related compounds and the like; antibiotics such astetracycline, chlortetracycline, bacitracin, neomycin, polymyxin,gramicidin, oxytetracycline, chloramphenicol, gentamycin, erythromycinand the like; anti-infectives; antibacterials such as sulfonamides,sulfacetamide, sulfamethizole, sulfisoxazole; nitrofurazone, sodiumpropionate and the like; antiallergenics such as antazoline,methapyriline, chlorpheniramine, pyrilamine, prophenpyridamine and thelike; anti-inflammatories such as hydrocortisone, hydrocortisoneacetate, dexamethasone 21-phosphate, fluocinolone, medrysone,methylprednisolone, prednisolone 21-phosphate, prednisolone acetate,fluoromethalone, betamethasone, triminolone and the like; miotics;anti-cholinesterase such as pilocarpine, eserine salicylate, carbachol,di-isopropyl fluorophosphate, phospholine iodine, demecarium bromide andthe like; miotic agents; mydriatics such as atropine sulfate,cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine,hydroxyamphetamine and the like; svmpathomimetics such as epinephrineand the like; and prodrugs such as, for example, those described inDesign of Prodrugs, edited by Hans Bundgaard, Elsevier ScientificPublishing Co., Amsterdam, 1985. In addition to the foregoing agents,other agents suitable for treating, managing, or diagnosing conditionsin a mammalian organism may be entrapped in the copolymer andadministered using the drug delivery systems of the current invention.Once again, reference may be made to any standard pharmaceuticaltextbook such as, for example, Remington's Pharmaceutical Sciences forpharmaceutically active agents.

Any pharmaceutically acceptable form of the foregoing therapeuticallyactive agent may be employed in the practice of the present invention,e.g., the free base; free acid; pharmaceutically acceptable salts,esters or amides thereof, e.g., acid additions salts such as thehydrochloride, hydrobromide, sulfate, bisulfate, acetate, oxalate,valerate, oleate, palmitate, stearate, laurate, borate, benzoate,lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate,succinate, tartrate, ascorbate, glucoheptonate, lactobionate, and laurylsulfate salts and the like; alkali or alkaline earth metal salts such asthe sodium, calcium, potassium and magnesium salts and the like;hydrates; enantiomers; isomers; stereoisomers; diastereoisomers;tautomers; polymorphs, mixtures thereof, prodrugs thereof or racematesor racemic mixtures thereof.

Additional agents that can be used with the present methods utilizinglacrimal implants include, but are not limited to, drugs that have beenapproved under Section 505 of the United States Federal Food, Drug, andCosmetic Act or under the Public Health Service Act, some of which canbe found at the U.S. Food and Drug Administration (FDA) websitehttp://www.accessdata.fda.gov/scripts/cder/drugsatfda/index. The presentlacrimal implants can also be used with drugs listed in the Orange Book,either in paper or in electronic form, which can be found at the FDAOrange Book website (http://www.fda.gov/cder/ob/)), that has or recordsthe same date as, earlier date than, or later date than, the filing dateof this patent document. For example, these drugs can include, amongothers, dorzolamide, olopatadine, travoprost, bimatoprost, latanoprost,cyclosporin, brimonidine, moxifloxacin, tobramycin, brinzolamide,aciclovir timolol maleate, ketorolac tromethamine, prednisolone acetate,sodium hyaluronate, nepafenac, bromfenac, diclofenac, flurbiprofen,suprofenac, binoxan, patanol, dexamethasone/tobramycin combination,moxifloxacin, or acyclovir.

Further discussion of drugs or other agents can be found incommonly-owned U.S. Patent Application Publication No. 2009/0104248,U.S. Patent Application Publication No. 2010/0274204, and U.S. PatentApplication Publication No. 2009/0105749, which are herein incorporatedby reference in its entirety.

Prostaglandins

Prostaglandins are regarded as potent ocular hypertensives; however,evidence accumulated in the last decade shows that some prostaglandinsare highly effective ocular hypotensive agents and are ideally suitedfor the long-term medical management of glaucoma (see, for example,Bito, L. Z. Biological Protection with Prostaglandins Cohen, M. M., ed.,Boca Raton, Fla., CRC Press Inc., 1985, pp. 231-252; and Bito, L. Z.,Applied Pharmacology in the Medical Treatment of Glaucomas Drance, S. M.and Neufeld, A. H. eds., New York, Grune & Stratton, 1984, pp. 477-505).Such prostaglandins include PGF2α, PGF_(1α), PGE₂, and certainlipid-soluble esters, such as C₁ to C₅ alkyl esters, e.g. 1-isopropylester, of such compounds.

Thus, in certain embodiments, the therapeutic agent is a prostaglandin,including derivatives thereof. Prostaglandins are derivatives ofprostanoic acid. Various types of prostaglandins are known, depending onthe structure and substituents carried on the alicyclic ring of theprostanoic acid skeleton. Further classification is based on the numberof unsaturated bonds in the side chains indicated by numericalsubscripts after the generic type of prostaglandin (e.g., prostaglandinE₁ (PGE₁), prostaglandin E₂ (PGE₂)), and on the configuration of thesubstituents on the alicyclic ring indicated by α or β (e.g.prostaglandin F₂α (PGF₂α)). Any of these prostaglandins are of use inthe present invention.

An exemplary therapeutic agent for use in the methods described hereinis latanoprost. Latanoprost is a prostaglandin F_(2α) analogue. Itschemical name is isopropyl-(Z)-7[(1R,2R,3R,5S)3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoate.Its molecular formula is C₂₆H₄₀O₅ and its chemical structure is:

Latanoprost is a colorless to slightly yellow oil that is very solublein acetonitrile and freely soluble in acetone, ethanol, ethyl acetate,isopropanol, methanol and octanol. It is practically insoluble in water.

Latanoprost is believed to reduce intraocular pressure (IOP) byincreasing the outflow of aqueous humor. Studies in animals and mansuggest that the main mechanism of action is increased uveoscleraloutflow of aqueous fluid from the eyes. Latanoprost is absorbed throughthe cornea where the isopropyl ester prodrug is hydrolyzed to the acidform to become biologically active. Studies in man indicate that thepeak concentration in the aqueous humor is reached about two hours aftertopical administration.

Xalatan® latanoprost ophthalmic solution is a commercially availableproduct indicated for the reduction of elevated IOP in patients withopen-angle glaucoma or ocular hypertension. The amount of latanoprost inthe commercially available product Xalatan® is approximately 1.5micrograms/drop, which is the recommended daily total dose oflatanoprost to one eye. As described above, eye drops, though effective,can be inefficient and require multiple applications to maintain thetherapeutic benefit. Low patient compliance compounds these effects.

In various embodiments, the prostaglandin is latanoprost. In anillustrative embodiment, the unit dosage format includes from 40 μg to100 μg of the therapeutic agent. In an exemplary embodiment, the implantincludes about 46 μg or about 95 μg of latanoprost.

In an exemplary embodiment, the implant of the invention is a member ofa pair of implants. In various embodiments, the pair of implants isconfigured as a unit dosage. In various embodiments, the implant isformatted as a unit dosage of an antiglaucoma agent. In an exemplaryembodiment, the antiglaucoma agent is a prostaglandin. In variousembodiments, the prostaglandin is latanoprost. In an illustrativeembodiment, the unit dosage format includes from 40 μg to 100 μg of thetherapeutic agent. In an exemplary embodiment, the unit dosage is 141 μgof latanoprost. In an exemplary embodiment, one implant includes about46 μg of latanoprost and the other includes about 95 μg of latanoprost.In an exemplary embodiment, the unit dosage is a unit dosage for botheyes, including four implants as described herein.

In an exemplary embodiment, the implant of the invention is a member ofa pair of implants. In various embodiments, the pair of implants isconfigured as a unit dosage. In various embodiments, the implant isformatted as a unit dosage of an antiglaucoma agent. In an exemplaryembodiment, the antiglaucoma agent is a prostaglandin. In variousembodiments, the prostaglandin is latanoprost. In an illustrativeembodiment, the unit dosage format includes from 40 μg to 100 μg of thetherapeutic agent. In an exemplary embodiment, the unit dosage is 190 μgof latanoprost. In an exemplary embodiment, each implant includes about95 μg of latanoprost. In an exemplary embodiment, the unit dosage is aunit dosage for both eyes, including four implants as described herein.

In an exemplary embodiment, the implant of the invention is a member ofa pair of implants. In various embodiments, the pair of implants isconfigured as a unit dosage. In various embodiments, the implant isformatted as a unit dosage of an antiglaucoma agent. In an exemplaryembodiment, the antiglaucoma agent is a prostaglandin. In variousembodiments, the prostaglandin is latanoprost. In an illustrativeembodiment, the unit dosage format includes from 40 μg to 100 μg of thetherapeutic agent. In an exemplary embodiment, the unit dosage is 95 μgof latanoprost. In an exemplary embodiment, a first implant includesabout 95 μg of latanoprost and a second implant does not includelatanoprost (e.g. a blank implant). In an exemplary embodiment, the unitdosage is a unit dosage for both eyes, including four implants asdescribed herein.

In an alternative embodiment, the implant of the invention is a singleimplant configured as a unit dosage. In various embodiments, the implantis formatted as a unit dosage of an antiglaucoma agent. In an exemplaryembodiment, the antiglaucoma agent is a prostaglandin. In variousembodiments, the prostaglandin is latanoprost. In an illustrativeembodiment, the unit dosage format includes from 40 μg to 100 μg of thetherapeutic agent. In an exemplary embodiment, the unit dosage is 95 μgof latanoprost. In an exemplary embodiment, a first implant includesabout 95 μg of latanoprost and is inserted into the upper punctum whileno implant is inserted into the lower punctum. In an exemplaryembodiment, the unit dosage is a unit dosage for both eyes, includingtwo implants as described herein.

Actual dosage levels of the pharmaceutically active agent(s) in the drugdelivery systems of use in the present invention may be varied to obtainan amount of the pharmaceutically active agent(s) that is effective toobtain a desired therapeutic response for a particular system and methodof administration. The selected dosage level therefore depends upon suchfactors as, for example, the desired therapeutic effect, the route ofadministration, the desired duration of treatment, and other factors.The total daily dose of the pharmaceutically active agent(s)administered to a host in single or divided doses can vary widelydepending upon a variety of factors including, for example, the bodyweight, general health, sex, diet, time and route of administration,rates of absorption and excretion, combination with other drugs, theseverity of the particular condition being treated, etc. In certainembodiments, the amounts of pharmaceutically active agent(s) present inthe drug delivery systems of the present invention can range from about0.1% w/w to about 60% w/w. In one embodiment, the amounts ofpharmaceutically active agent(s) present in the present drug deliverysystems can range from about 1% w/w to about 50% w/w.

The therapeutic agents are formulated as a sustained release formulationand incorporated into the lacrimal implants. This sustained releaseformulation may either be in the form of a drug core or dispersedthroughout the lacrimal implant. In this instance the lacrimal implantmay be saturated and/or impregnated with the therapeutic agent. However,before describing the sustained release formulations the lacrimalimplants will first be described in detail.

2) Lacrimal Implants

The implant can be one of any number of different designs that releaseslatanoprost or other intraocular pressure-reducing therapeutic agent(s)for a sustained period of time. The disclosures of the following patentdocuments, which describe example implant structure or processingembodiments for use in the methods of embodiments of the currentinvention and methods of making those implants, are incorporated hereinby reference in their entirety: U.S. Application Ser. No. 60/871,864(filed Dec. 26, 2006 and entitled Nasolacrimal Drainage System Implantsfor Drug Therapy); U.S. application Ser. No. 11/695,537 (filed Apr. 2,2007 and entitled Drug Delivery Methods, Structures, and Compositionsfor Nasolacrimal System); U.S. U.S. application Ser. No. 12/332,219(filed Dec. 10, 2008 and entitled Drug Delivery Methods, Structures, andCompositions for Nasolacrimal System); U.S. Application Ser. No.60/787,775 (filed Mar. 31, 2006 and entitled Nasolacrimal DrainageSystem Implants for Drug Therapy); U.S. application Ser. No. 11/695,545(filed Apr. 2, 2007 and entitled Nasolacrimal Drainage System Implantsfor Drug Therapy); U.S. Application Ser. No. 60/585,287 (filed Jul. 2,2004 and entitled Treatment Medium Delivery Device and Methods forDelivery of Such Treatment Mediums to the Eye Using Such a DeliveryDevice); U.S. application Ser. No. 11/571,147 (filed Dec. 21, 2006 andentitled Treatment Medium Delivery Device and Methods for Delivery ofSuch Treatment Mediums to the Eye Using Such a Delivery Device); U.S.Application Ser. No. 60/970,696 (filed Sep. 7, 2007 and entitledExpandable Nasolacrimal Drainage System Implants); U.S. Application Ser.No. 60/974,367 (filed Sep. 21, 2007 and entitled Expandable NasolacrimalDrainage System Implants); U.S. Application Ser. No. 60/970,699 (filedSep. 7, 2007 and entitled Manufacture of Drug Cores for SustainedRelease of Therapeutic Agents); U.S. Application Ser. No. 60/970,709(filed Sep. 7, 2007 and entitled Nasolacrimal Drainage System Implantsfor Drug Delivery); U.S. Application Ser. No. 60/970,720 (filed Sep. 7,2007 and entitled Manufacture of Expandable Nasolacrimal Drainage SystemImplants); U.S. Application Ser. No. 60/970,755 (filed Sep. 7, 2007 andentitled Prostaglandin Analogues for Implant Devices and Methods); U.S.Application Ser. No. 60/970,820 (filed Sep. 7, 2007 and entitledMultiple Drug Delivery Systems and Combinations of Drugs with PunctalImplants); U.S. Application Ser. No. 61/066,223 (filed Feb. 18, 2008 andentitled Lacrimal Implants and Related Methods); U.S. Application Ser.No. 61/049,347 (filed Apr. 30, 2008 and entitled Lacrimal Implants andRelated Methods); U.S. Application Ser. No. 61/033,211 (filed Mar. 3,2008 and entitled Lacrimal Implants and Related Methods); U.S.Application Ser. No. 61/049,360 (filed Apr. 30, 2008 and entitledLacrimal Implants and Related Methods); U.S. Application Ser. No.61/052,595 (filed May 12, 2008 and entitled Lacrimal Implants andRelated Methods); U.S. Application Ser. No. 61/075,309 (filed Jun. 24,2008 and entitled Lacrimal Implants and Related Methods); U.S.Application Ser. No. 61/154,693 (filed Feb. 23, 2009 and entitledLacrimal Implants and Related Methods); U.S. Application Ser. No.61/209,036 (filed Mar. 2, 2009 and entitled Lacrimal Implants andRelated Methods); U.S. Application Ser. No. 61/209,630 (filed Mar. 9,2009 and entitled Lacrimal Implants and Related Methods); U.S.Application Ser. No. 61/036,816 (filed Mar. 14, 2008 and entitledLacrimal Implants and Related Methods); U.S. Application Ser. No.61/271,862 (filed Jul. 27, 2009 and entitled Lacrimal Implants andRelated Methods); U.S. Application Ser. No. 61/252,057 (filed Oct. 15,2009 and entitled Lacrimal Implants and Related Methods); U.S.application Ser. No. 12/710,855 (filed Feb. 23, 2010 and entitledLacrimal Implants and Related Methods); U.S. Application Ser. No.60/871,867 (filed Dec. 26, 2006 and entitled Drug Delivery Implants forInhibition of Optical Defects); U.S. application Ser. No. 14/521,543(filed Dec. 31, 2009 and entitled Drug Delivery Implants for Inhibitionof Optical Defects); U.S. Application Ser. No. 61/052,068 (filed May 9,2008 and entitled Sustained Release Delivery of Latanoprost to TreatGlaucoma); U.S. Application Ser. No. 61/052,113 (filed May 9, 2008 andentitled Sustained Release Delivery of Latanoprost to Treat Glaucoma);U.S. Application Ser. No. 61/108,777 (filed Oct. 27, 2008 and entitledSustained Release Delivery of Latanoprost to Treat Glaucoma); U.S.application Ser. No. 12/463,279 (filed May 8, 2009 and entitledSustained Release Delivery of Active Agents to Treat Glaucoma and OcularHypertension); U.S. Application Ser. No. 61/049,337 (filed Apr. 30, 2008and entitled Lacrimal Implants and Related Methods); U.S. applicationSer. No. 12/432,553 (filed Apr. 29, 2009 and entitled Composite LacrimalInsert and Related Methods); U.S. Application Ser. No. 61/049,317 (filedApr. 30, 2008 and entitled Drug-Releasing Polyurethane Lacrimal Insert);U.S. application Ser. No. 12/378,710 (filed Feb. 17, 2009 and entitledLacrimal Implants and Related Methods); U.S. Application Ser. No.61/075,284 (filed Jun. 24, 2008 and entitled Combination Treatment ofGlaucoma); U.S. application Ser. No. 12/490,923 (filed Jun. 24, 2009 andentitled Combination Treatment of Glaucoma); U.S. Application Ser. No.61/134,271 (filed Jul. 8, 2008 and entitled Lacrimal Implant BodyIncluding Comforting Agent); U.S. application Ser. No. 12/499,605 (filedJul. 8, 2009 and entitled Lacrimal Implant Body Including ComfortingAgent); U.S. Application Ser. No. 61/057,246 (filed May 30, 2008 andentitled Surface Treatment of Implants and Related Methods); U.S.Application Ser. No. 61/132,927 (filed Jun. 24, 2008 and entitledSurface Treated Implantable Articles and Related Methods); U.S.application Ser. No. 12/283,002 (filed Sep. 5, 2008 and entitled SurfaceTreated Implantable Articles and Related Methods); U.S. application Ser.No. 12/231,989 (filed Sep. 5, 2008 and entitled Lacrimal Implants andRelated Methods); U.S. Application Ser. No. 61/049,317 (filed Apr. 30,2008 and entitled Drug-Releasing Polyurethane Lacrimal Insert); U.S.application Ser. No. 12/231,986 (filed Sep. 5, 2008 and entitled DrugCores for Sustained Release of Therapeutic Agents); U.S. ApplicationSer. No. 61/050,901 (filed May 6, 2008 and entitled Punctum PlugDetection); U.S. application Ser. No. 12/231,987 (filed Sep. 5, 2008 andentitled Lacrimal Implant Detection); U.S. Application Ser. No.61/146,860 (filed Jan. 23, 2009 and entitled Sustained Release Deliveryof One or More Anti-Glaucoma Agents); U.S. Application Ser. No.61/152,909 (filed Feb. 16, 2009 and entitled Sustained Release Deliveryof One or More Anti-Glaucoma Agents); U.S. Application Ser. No.61/228,894 (filed Jul. 27, 2009 and entitled Sustained Release Deliveryof One or More Anti-Glaucoma Agents); U.S. Application Ser. No.61/277,000 (filed Sep. 18, 2009 and entitled Drug Cores for SustainedOcular Release of Therapeutic Agents); U.S. application Ser. No.12/692,452 (filed Jan. 22, 2010 and entitled Sustained Release Deliveryof One or More Agents); U.S. Application Ser. No. 61/283,100 (filed Nov.27, 2009 and entitled Lacrimal Implants Including Split and InsertableDrug Core); International Application Serial No. PCT/US2010/058129(filed Nov. 26, 2010, published as WO 2011/066479 and entitled LacrimalImplants Including Split and Insertable Drug Core); U.S. ApplicationSer. No. 61/139,456 (filed Dec. 19, 2008 and entitled SubstanceDelivering Punctum Implants and Methods); U.S. application Ser. No.12/643,502 (filed Dec. 21, 2009 and entitled Substance DeliveringPunctum Implants and Methods); U.S. application Ser. No. 10/825,047(filed Apr. 15, 2004 and entitled Drug Delivery via Punctal Plug); U.S.application Ser. No. 12/604,202 (filed Oct. 22, 2009 and entitled DrugDelivery via Ocular Implant); International Application Serial No.PCT/US2005/023848 (filed Jul. 1, 2005, published as WO 2006/014434 andentitled Treatment Medium Delivery Device and Methods for Delivery);International Application Serial No. PCT/US2007/065792 (filed Apr. 2,2007, published as WO 2007/115261 and entitled Drug Delivery Methods,Structures, and Compositions for Nasolacrimal System); and InternationalApplication Serial No. PCT/US2007/065789 (filed Apr. 2, 2007, publishedas WO 2007/115259 and entitled Nasolacrimal Drainage System Implants forDrug Therapy).

Occlusive Element

In an exemplary embodiment, the methods of the invention use an implanthaving an occlusive element. An occlusive element can be mounted to andexpandable with the retention structure, described below, to inhibittear flow. An occlusive element may inhibit tear flow through the lumen,and the occlusive element may cover at least a portion of the retentionstructure to protect the lumen from the retention structure. Theocclusive element comprises an appropriate material that is sized andshaped so that the implant can at least partially inhibit, even block,the flow of fluid through the hollow tissue structure, for examplelacrimal fluid through the canaliculus. The occlusive material may be athin walled membrane of a biocompatible material, for example silicone,that can expand and contract with the retention structure. The occlusiveelement is formed as a separate thin tube of material that is slid overthe end of the retention structure and anchored to one end of theretention structure as described above. Alternatively, the occlusiveelement can be formed by dip coating the retention structure in abiocompatible polymer, for example silicone polymer. The thickness ofthe occlusive element can be in a range from about 0.01 mm to about 0.15mm, and often from about 0.05 mm to 0.1 mm.

Retention

In various embodiments of the methods of the invention, an implantincluding a retention structure is employed to retain the implant in thepunctum or canaliculus. The retention structure is attached to orintegral with the implant body. The retention structure comprises anappropriate material that is sized and shaped so that the implant can beeasily positioned in the desired tissue location, for example, thepunctum or canaliculus. In some embodiments, the drug core may beattached to the retention structure via, at least in part, the sheath.In some embodiments, the retention structure comprises a hydrogelconfigured to expand when the retention structure is placed in thepunctum. The retention structure can comprise an attachment memberhaving an axially oriented surface. In some embodiments, expansion ofthe hydrogel can urge against the axially oriented surface to retain thehydrogel while the hydrogel is hydrated. In some embodiments, theattachment member can comprise at least one of a protrusion, a flange, arim, or an opening through a portion of the retention structure. In someembodiments, the retention structure includes an implant body portionsize and shape to substantially match an anatomy of the punctum andcanaliculus.

The retention structure may have a size suitable to fit at leastpartially within the canalicular lumen. The retention structure can beexpandable between a small profile configuration suitable for insertionand a large profile configuration to anchor the retention structure inthe lumen, and the retention structure can be attached near the distalend of the drug core. In specific embodiments, the retention structurecan slide along the drug core near the proximal end when the retentionstructure expands from the small profile configuration to the largeprofile configuration. A length of the retention structure along thedrug core can be shorter in the large profile configuration than thesmall profile configuration.

In some embodiments, the retention structure is resiliently expandable.The small profile may have a cross section of no more than about 0.2 mm,and the large profile may have a cross section of no more than about 2.0mm. The retention structure may comprise a tubular body having armsseparated by slots. The retention structure can be disposed at leastpartially over the drug core.

In some embodiments, the retention structure is mechanically deployableand typically expands to a desired cross sectional shape, for examplewith the retention structure comprising a super elastic shape memoryalloy such as Nitinol™. Other materials in addition to Nitinol™ can beused, for example resilient metals or polymers, plastically deformablemetals or polymers, shape memory polymers, and the like, to provide thedesired expansion. In some embodiments polymers and coated fibersavailable from Biogeneral, Inc. of San Diego, Calif. may be used. Manymetals such as stainless steels and non-shape memory alloys can be usedand provide the desired expansion. This expansion capability permits theimplant to fit in hollow tissue structures of varying sizes, for examplecanaliculae ranging from 0.3 mm to 1.2 mm (i.e. one size fits all).Although a single retention structure can be made to fit canaliculaefrom 0.3 to 1.2 mm across, a plurality of alternatively selectableretention structures can be used to fit this range if desired, forexample a first retention structure for canaliculae from 0.3 to about0.9 mm and a second retention structure for canaliculae from about 0.9to 1.2 mm. The retention structure has a length appropriate to theanatomical structure to which the retention structure attaches, forexample a length of about 3 mm for a retention structure positioned nearthe punctum of the canaliculus. For different anatomical structures, thelength can be appropriate to provide adequate retention force, e.g. 1 mmto 15 mm lengths as appropriate.

Although the implant body may be attached to one end of the retentionstructure as described above, in many embodiments the other end of theretention structure is not attached to the implant body so that theretention structure can slide over the implant body including the sheathbody and drug core while the retention structure expands. This slidingcapability on one end is desirable as the retention structure may shrinkin length as the retention structure expands in width to assume thedesired cross sectional width. However, it should be noted that manyembodiments may employ a sheath body that does not slide in relative tothe core.

In many embodiments, the retention structure can be retrieved fromtissue. A projection, for example a hook, a loop, or a ring, can extendfrom a portion of the implant body to facilitate removal of theretention structure.

In some embodiments the sheath and retention structure can comprise twoparts.

In certain embodiments, the lacrimal implants used with the presentmethods have exceptional retention properties, and are retained in thepunctum and canaliculus for a period that is enhanced relative to acommercially available plug (FIG. 9) based upon the percentage of eyesin which an implant was implanted retaining the implant over a selectedtime period. In other embodiments, the retention properties of thepresent lacrimal implants of FIG. 33 were evaluated demonstratingsuperior retention rates over a period of weeks. See, FIGS. 34-39.

In an exemplary embodiment, the method of the invention uses a lacrimalimplant configured to remain implanted in a punctum for at least about 1week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8, weeks, 9weeks 10 weeks, 11 weeks, or at least about 12 weeks or more. In anexemplary embodiment, the lacrimal implant is configured to be retainedby the puncta for the duration of the intended sustained release of thetherapeutic agent. In various embodiments, the duration of the intendedsustained release of the therapeutic agent is at least about 1 week, 2weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8, weeks, 9 weeks 10weeks, 11 weeks, or at least about 12 weeks or more. In variousembodiments at least about 95%, at least about 90%, at least about 85%or at least about 80% of the implanted implants are retained for theduration of the intended controlled release of the therapeutic agent. Inan exemplary embodiment, the implant is retained by the puncta for alength of time to show therapeutic efficacy.

In various embodiments, the present invention provides for the use ofimplants having structural features that enhance the retention of theimplant in a puncta. Amongst other features, the heel of the presentimplant (e.g., 330) is configured to come to rest in the lacrimalcanaliculus ampulla (e.g., 252), effectively locking the implant intoplace. However, the Applicants have recognized that to prevent rotationand relative movement of the implanted device, which plays a role in thedisplacement of the device, a first member was needed to maintain theheel in the ampula. Thus, the first member, e.g., 305, is configured tostabilize the punctal plug within the lacrimal canaliculus, preventrotation and maintain positioning of the plug when the surroundingtissue moves.

FIGS. 3-6 illustrate exemplary embodiments of lacrimal implants of usein the methods of the invention. The exemplary implants are insertablethrough a lacrimal punctum 212, 214 and into its associated canaliculus208, 210. Exemplary lacrimal implants of use in the present inventioncomprise a first member, a second member and a heel, such as the firstmember 305, the second member 310 and the third member or heel 330depicted in FIG. 3A. Exemplary lacrimal implants further comprise a borethat is formed in the heel, for example, the bore 385 formed in thethird member or heel 330 in FIG. 3A. In some embodiments, exemplarylacrimal implants further comprise a cavity 458 (e.g., lacrimal implantsillustrated in FIG. 4A).

Referring to FIG. 3A, where a perspective view of an exemplary lacrimalimplant 300 of use in the present methods is depicted, the first member305 is characterized by a first axis A and the second member 310 ischaracterized by a second axis B.

The third member or heel 330 is configured to connect the first member305 and the second member 310 at a first angle θ₁, where θ₁ is definedby the first axis A with respect to the second axis B. For instance, inFIG. 3A, the first angle θ₁ refers to the angle originating at the firstaxis A and turning counterclockwise from the first axis A to the secondaxis B. In some embodiments, the first axis A and the second axis B arein the same plane and intersect each other. In some embodiments, thefirst axis A is in a plane other than the plane of the second axis B,and the first axis A and the second axis B do not intersect. In suchembodiments, the first angle θ₁ refers to the angle defined by aparallel line of the first axis A with respect to the second axis B.This parallel line of the first axis A lies in the same plane as thesecond axis and intersects with the second axis.

In some embodiments, the first angle θ₁ is from about 30 degrees toabout 150 degrees, from about 45 degrees to about 135 degrees, or fromabout 75 degrees to about 105 degrees. For example, in some embodiments,the first angle θ₁ is approximately 90 degrees.

In some embodiments, the overall dimension of the implant along thefirst axis is from about 4 mm to about 8 mm. In an exemplary embodiment,the overall dimension along the first axis is about 5 mm to about 7 mm.In various embodiments, the overall dimension along the first axis isabout 6.3 mm.

In various embodiments, the overall dimension along the second axis B isfrom about 1 mm to about 3 mm, e.g., from about 1.2 mm to about 1.9 mm.

In some embodiments, the overall dimension along the first axis isapproximately 6.3 mm and the overall dimension along the second axis isapproximately 1.2 mm. In various embodiments, the overall dimensionalong the first axis is approximately 6.3 mm and the overall dimensionalong the second axis is approximately 1.9 mm. In some embodiments, theoverall dimension along the first axis is approximately 4.8 mm and theoverall dimension along the second axis is approximately 1.9 mm.

First Member 305

In some embodiments, the first member 305 is configured to extend into acanaliculus, while the second member 310 is configured to reside in thevertical portion 220, 222 of the canaliculus and to extend to theopening of, or out of the opening of, the associated puncta. When alacrimal implant 300 of such configuration is inserted into acanaliculus, the intersection of the first axis A and the second axis Bresides generally at a curvature of the canaliculus, such as thecanaliculus curvature 250 in FIG. 2. In some embodiments, the firstmember 305 and the second member 310 are connected at the first angle,and that angle is at least about 45 degree, thereby forming an angledintersection between the first member and the second member. In variousembodiments, when the lacrimal implant 300 is positioned in the lacrimalcanaliculus, at least a portion of the angled intersection is biasedagainst a canaliculus curvature of the lacrimal canaliculus. In thisembodiment, the lacrimal implant 300 uses anatomical structures tofacilitate the retention of the implanted lacrimal implant 300.

FIG. 3B depicts a side view of an exemplary lacrimal implant 300 of theinvention. In some embodiments, the first member 305 includes anintermediate segment 315, a tip segment or tip 325, and a forwardsegment 320 in between the forward segment and tip segment. While theintermediate segment 315 is configured to be connected to the secondmember 310 by the third member or heel 330, the tip segment or tip 325is configured to be inserted through a punctum prior to the other twosegments of the first member 305 and prior to the other members of thelacrimal implant 300.

In some embodiments, the intermediate segment 315, the forward segment320 and the tip segment or tip 325 are distinguishable from each otherin general by their shapes. For example, in some embodiments, theintermediate segment 315 has a generally cylindrical shape with adiameter that is larger than the diameter of the tip segment or tip 325.In various embodiments, the forward segment 320 is tapered and has aconical shape, such that the forward segment 320 connects theintermediate segment 315 at one end and the tip segment or tip 325 atthe other end. In some embodiments, the transition from the intermediatesegment 315 to the forward segment 320 or the transition from theforward segment 320 to the tip segment or tip 325 is gradual and smoothsuch that no distinguishable edge exists at the transition.

In some embodiments, the intermediate segment 315 has a cylindricalshape. In various embodiments, the intermediate segment has a circularcross section, an elliptic cross section, or a polygonal cross section.The intermediate segment 315 is of any useful combination of length anddiameter.

In some embodiments, the intermediate segment 315 has a diameter that isfrom about 0.4 mm to about 0.8 mm. For example, in some embodiments thediameter of the intermediate segment 315 is from about 0.53 mm to about0.63 mm. In some embodiments, the intermediate segment 315 has a lengthalong the first axis A that is from about 0.5 mm to about 3.5 mm. Forexample, in some embodiments the length of the intermediate segment 315is from about 1 mm to about 2.8 mm.

In some embodiments, the tip segment or tip 325 is substantially asemi-sphere, or a portion of a semi-sphere. In exemplary embodiments,the semi-sphere, or portion therapy, has a radius that is from about0.05 mm to about 0.3 mm. For example, in some embodiments, the radius ofthe tip segment or tip 325 is approximately 0.20 mm.

In some embodiments, the forward segment 320 has a conicalconfiguration, tapering from the diameter of the intermediate segment315 as it approaches the tip segment or tip 325. In some embodiments,the forward segment 320 is short and is tapered steeply, thus forming awider taper angle. The forward segment 320 can also be long and taperedmore gradually, thus forming a narrower taper angle. The tapering angleθ₃ is illustrated in FIG. 3E. In some embodiments, the tapering angle θ₃is from about 2° to about 10°. For example, in some embodiments thetapering angle θ₃ is from about 3.8° to about 7.8°. In some embodiments,θ₃ is about 7.8°. In some embodiments, the forward segment 320 has alength along the first axis A that is from about 1 mm to about 5 mm. Forexample in some embodiments the length of forward segment 320 is fromabout 1.7 mm to about 3.5 mm.

Second Member 310

Referring to FIG. 3B, in some embodiments of implants of use in thepresent method, the second member 310 includes an upright segment 335that extends from the third member or heel 330 generally along thedirection of the second axis B. In various embodiments, the secondmember 310 further includes a head segment 340 that attaches to theupright segment 335 at an end opposite to the third member or heel 330.In some embodiments, the second member 310 is configured such that theupright segment 335 resides in the vertical portion of the canaliculuswhile the head segment 340 contacts the tissue surrounding the exteriorof the punctum when the lacrimal implant 300 is positioned in thelacrimal canaliculus. In an exemplary embodiment, illustrated in FIGS.3A-3F, the upright segment 335 has a cylindrical shape and the headsegment 340 has an oval or oblong configuration. However, it will beappreciated that any other suitable shapes or configurations can be usedand are within the scope of the present invention. For example, invarious embodiments, the upright segment 335 is configured to be aconical; the head segment 340 is configured to have a circular,elliptical or polygonal cross section.

In some embodiments, the upright segment 335 has a characteristicdiameter that is from about 0.7 mm to about 0.9 mm. For example, in someembodiments, the characteristic diameter of the upright segment 335 isabout 0.8 mm.

In some embodiments, the upright segment 335 has a length in thedirection of the second axis B that is from about 0.7 mm to about 1.5mm. For example, in some embodiments the length of upright segment 335along the direction of the second axis B is about 0.9 mm.

Generally, the head segment 340 has a cross section characterized by aminor axis and a major axis. The minor axis and the major axis refer tothe shortest characteristic diameter and the longest characteristicdiameter of the cross section, respectively. As such, the minor axis isequal to or less than the major axis. For instance, in some embodimentswhere the head segment 340 has a circular cross section, the minor axisand the major axis are of equal length. In various embodiments, the headsegment 340 has an oval or oblong cross section, and the minor axis isshorter than the major axis. In some embodiments, the head segment 340is elongated in a direction that is parallel to the first axis A. Themajor axis indicates the extension of the first member 305 andfacilitates positioning of the lacrimal implant 300 in the punctum andcanalinculus. In some embodiments, the major axis is from about 1.5 mmto about 2.5 mm. In various embodiments, the minor axis is from about 1mm to about 1.5 mm. For example, in some embodiments, the major axis andthe minor axis head segment 340 are approximately 1.9 mm and 1.3 mmrespectively. In some embodiments, the head segment 340 has a thicknessin the direction of the second axis that is from about 0.2 mm to about0.4 mm. For example, in some embodiments, the thickness of the headsegment 340 in the direction of the second axis is approximately 0.3 mm.

Referring still to FIG. 3B, exemplary head segment 340 comprises anunder-surface 350 facing towards the third member or heel 330 and anouter-surface 355 that faces away from the third member or heel 330.Exemplary head segment 340 further comprises an edge surface 345 thatcouples the under-surface 350 and the outer-surface 355. The distancebetween the under-surface 350 and the outer-surface 355 can be readilyvaried. In some embodiments, the distance is from about 0.2 mm to about0.4 mm.

In some embodiments, the outer-surface 355 is smaller than theunder-surface 350 and is substantially flat. In various embodiments, theedge surface 345 is tapered, curved, angular, or multifaceted. In someembodiments, the edge surface 345 has a radius of curvature that is fromabout 0.2 mm to about 0.7 mm. In some embodiments, the under-surface 350is in general flat and is configured to contact the exterior tissuesurrounding the punctum when the lacrimal implant 300 is positioned inthe lacrimal canaliculus.

Third Member or Heel 330

In some embodiments, the third member or heel 330 includes an uppersurface 360, a lower surface 365, and side surfaces 370. In theillustrated embodiments, the bore 385 extends from the upper surface 360into the third member or heel 330. In some embodiments, the uppersurface 360 and the lower surface 365 are substantially flat andseparated from each other by a distance. Such distance is readilyvariable and is typically about 0.3 mm to about 0.7 mm. For instance, insome embodiments, the upper surface 360 and the lower surface 365 areseparated by a distance that is from about 0.4 mm to 0.6 mm (e.g., about0.53 mm). In some embodiments, the upper surface 360 extends beyond theintersection with the second member 310. In some embodiments, the uppersurface 360 extends beyond the intersection with the second member 310for a distance that is from about 0.3 to about 0.6 mm. The upper surface360 can also be joined with the side surfaces 370. In variousembodiments, upper surface 360 and side surfaces 370 are joined by acurved intersection 380. In some embodiments, the curved intersection380 has a radius of curvature that is from about 0.04 mm to about 0.08mm.

Referring now to FIGS. 3D and 3F, in some embodiments, the third memberor heel 330 includes a heel connecting segment 375 configured to couplethe third member or heel 330 to the first member 305, or to theintermediate segment 315 of the first member 305. The heel connectingsegment 375 is of readily variable shape, including flat or curvedstructures. In FIG. 3F, a width of the heel connecting segment 375 inthe direction of the second axis B varies along the direction of thefirst axis A. For example, the heel connecting segment 375 has a smallerwidth at or near the side surfaces 370 than the diameter of theintermediate segment 315 of the first member 305. In some embodiments,at or near the intersection with the intermediate segment 315, the heelconnecting segment 375 increases the width and thus forms a notch asdepicted in FIG. 3F. It will be appreciated that the notch can be eitherdeeper or shallower along both the first axis A and the second axis Bbefore it meets the first member 305 or the second member 310.

A notch is not a required feature in the implants of the presentinvention. In some embodiments, the heel connecting segment 375 has thesame dimension as the diameter of the intermediate segment 315. Forexample, the thickness of the third member or heel 330 along the secondaxis B is equal to the diameter of the intermediate segment 315 of thefirst member 305. For example, in some embodiments, both the thicknessof the third member or heel 330 in the direction of the second axis Band the diameter of the intermediate segment 315 are from about 0.53 mmto about 0.63 mm. In such configurations, the third member or heel 330couples with the intermediate segment 315 without forming a notch, asillustrated by the alternative heel connecting segment 675 in FIG. 6.

By way of illustration, the third member or heel 330 depicted in FIGS.3A-3F is substantially parallel to the first axis A of the first member305. It would be appreciated that this is unnecessary. In someembodiments, the third member or heel 330 can form an angle withrelation to the first axis A.

Bore 385

Exemplary structures of the bore 385 are detailed in FIGS. 3E and 3F,where a cross sectional view and a partial enlarged cross sectional viewof the lacrimal implant 300 are provided. The bore 385 is configured toreceive a tip or other protrusion of an external insertion tool forfacilitating insertion of the lacrimal implant 300 into a lacrimalpunctum. See FIG. 7. The configuration, including size, shape, angle(O₂) and position of the bore in the heel are readily adjustable tofacilitate the mating of the insertion tool with the bore, theflexibility of the heel, or the retention of the lacrimal implants.Depending on the purpose or use of the implant and the materials usedfor making the heel, the characteristics of the bore noted above arereadily varied. Configurations of the bore 385 disclosed herein areillustrative and any other suitable configurations are within the scopeof the present invention.

In FIG. 3F, an exemplary bore 385 is characterized by a third axis C anda second angle θ₂ that is defined by the first axis with respect to thethird axis A in a similar way as the first angle θ₁. In someembodiments, the second angle θ₂ is from about 15° to about 90°. Forexample, in some embodiments, the second angle θ₂ is about 45°.

In some embodiments, the bore 385 has a depth along the direction of thethird axis C that is from about 0.3 mm to about 0.7 mm. For example, insome embodiments the depth of the bore 385 is approximately 0.4 mm andin some embodiments is approximately 0.6 mm. The bore 385 may include abore shaft 390 that is generally cylindrical, with a circular,elliptical, oval, or polygonal cross section. The bore 385 may furtherinclude a bore tip 395 at which the bore shaft 390 terminates. Anexemplary bore tip 395 generally has a semispherical configuration. Insome embodiments, the bore shaft 390 has a characteristic diameter thatis from about 0.1 mm to about 0.3 mm. In some embodiments, thecharacteristic diameter of the bore is approximately 0.17 mm. As will beappreciated, the shapes, sizes, orientations disclosed in the presentapplication are illustrative, and any other suitable shapes, sizes, ororientations are within the scope of the present application. Inaddition, it will be appreciated that the opening of the bore can bepositioned closer to the second member or closer to the edge of theheel.

Cavity 458

FIG. 4A-4C illustrates an exemplary lacrimal implant 400 that isinsertable through a lacrimal punctum 212, 214 and into its associatedcanaliculus 208, 210. In FIG. 4A, the lacrimal implant 400 comprises acavity 458 that is configured to house a therapeutic agent core, alsoreferred to herein as a drug core, or other materials for release intoan eye or surrounding tissues for treatment of various ocular, sinus orother diseases.

In the illustrated exemplary embodiment, the cavity 458 is formed in thehead segment 340 and has an opening through the outer-surface 355. Thecavity 458 can be shallow such that it stays within the head segment340. The cavity 458 can be also deeper and extend beyond the headsegment 340 and into the upright segment 335. Illustrated exemplarycavity 458 is in general substantially cylindrical with a circular crosssection. Any other suitable configuration is within the scope of thepresent application. For example, in some embodiments, the cavity 458has a truncated spherical configuration, or has a cylindricalconfiguration with an oblong or a polygonal cross section.

In some embodiments, the cavity 458 has a depth in the direction of thesecond axis B that is about from 0.2 mm to about 1.4 mm. For example, insome embodiments, the depth of the cavity 458 is approximately 1.2 mm.In some embodiments, the cavity 458 has a diameter that is from about0.3 mm to about 0.7 mm. For example, in some embodiments the diameter ofthe cavity 458 is from about 0.42 mm to about 0.55 mm. In an exemplaryembodiment, the cavity 458 extends into the upright segment 335, and thediameter of the cavity 458 is smaller than the diameter of the uprightsegment 335.

Referring to FIG. 4C, the cavity 458 includes a bottom 482. In variousembodiments, the bottom 482 is rounded. In various embodiments, therounded bottom has a radius of curvature that is from about 0.03 mm toabout 0.07 mm.

FIG. 5 depicts exemplary configurations of the cavity 458. In FIG. 5,the cavity 458 includes a lip 584 or other retaining structurepositioned at the opening of the cavity 458. The lip 584 or the otherretaining structure are optionally configured to partially enclose thecavity 458, e.g, prevent a therapeutic agent core or other materialsfrom moving out of the cavity 458. In some embodiments, the lip 584 is asquare cross sectional annulus that extends down from the outer-surface355 into the cavity 458 and extends inwardly towards the center of theopening of the cavity 458. In some embodiments, the lip 584 is of a tabconfiguration and includes a plurality of spaced lips that extendinwardly into the opening of the cavity 458. The lip 584 may extenddownwardly from about 0.02 mm to about 0.1 mm and inwardly from about0.02 mm to about 0.1 mm. For example, in some embodiments, the lip 584extends about 0.05 mm downwardly or inwardly.

Formation of Lacrimal Implants

Exemplary lacrimal implants of use in methods of the present inventionare made of various materials including plastic, rubber, polymer, orcomposite. Exemplary lacrimal implants of the present invention formedfrom one or more material including plastic, rubber, polymer,composites, or other appropriate materials. In some embodiments, thelacrimal implants are formed from liquid silicone rubber. For instance,in exemplary embodiments, lacrimal implants are formed from a materialmarketed as NuSil 4840 liquid silicone rubber, NuSil 4870, or a mixtureincluding such a liquid silicone rubber. Examples of such a mixtureinclude a material marketed as 6-4800, which comprises NuSil 4840 withfrom about 1% to about 5%, e.g., from about 2% to about 4% 6-4800.

In some embodiments, the lacrimal implant is formed from biodegradablematerials, for instance, biodegradable elastic materials includingcross-linked polymers, such as poly (vinyl alcohol). In someembodiments, the lacrimal implant can comprise a co-polymer, such assilicone/polyurethane co-polymer, silicone/urethane, silicone/poly(ethylene glycol) (PEG), and silicone/2hydroxyethyl methacrylate (HEMA).As discussed in commonly-owned Utkhede et al., U.S. Patent PublicationNo. 2009/0104243, entitled “DRUG CORES FOR SUSTAINED RELEASE OFTHERAPEUTIC AGENTS,” filed Sep. 5, 2008, which is herein incorporated byreference in its entirety, urethane-based polymer and copolymermaterials allow for a variety of processing methods and bond well to oneanother.

The hardness of the material is selected to facilitate or alter theretention of the lacrimal implant within the lacrimal punctum and itsassociated canaliculus. Accordingly, in some embodiments, a materialhaving a durometer rating of from about 20D to about 80D, e.g., about30D to about 70D, e.g., from about 40D to about 60D is of use to adjustparameters such as patient comfort and retention. For example, in someembodiments, the durometer rating of the material used to form thelacrimal implants is approximately 40D. Materials other than thoseexemplified above providing a durometer rating for the lacrimal implantswithin the stated ranges, and particularly that is about 40D are also ofuse. In some embodiments, a harder material or softer material isutilized for the entire lacrimal implant or for portions thereof. Insuch case, the lacrimal implants are formed from the materials thatprovide a durometer rating of about 70D.

In some embodiments, the lacrimal implants of use in the present methodsare formed of multiple materials, where certain members or portions ofthe lacrimal implants are formed with materials having differentproperties. For example, in some embodiments the first member 305 isformed of a harder durometer rated material while the second member 310is formed of a softer durometer rated material. In some embodiments, thefirst member 305 is formed of a softer durometer rated material whilethe second member 310 is formed of a harder durometer rated material. Insome embodiments the third member or heel 330 is formed of a harderdurometer rated material than one or more parts of the remainder of thesecond member 310. In various embodiments, the third member or heel 330is formed of a softer durometer rated material than the remainder of thesecond member 310.

In certain embodiments, the implant comprises a contrast agent to aid indetection of the inserted lacrimal implant. See, US Patent PublicationNo. 2009/0099626, filed Sep. 5, 2008 entitled LACRIMAL IMPLANTDETECTION. In one embodiment, the contrast agent is a dye or pigment. Inanother embodiment, a green colorant is added during the manufacturingprocess of the lacrimal implant. In certain embodiments, this greencolorant is premixed with the NuSil liquid silicone rubber to form agreen lacrimal implant.

Exemplary implants of use in the invention can be formed by methodsknown in the art, including, but not limited to, machining a blank tothe desired shape and size and molding the material forming the implant.

Insertion Tools

Installing the lacrimal implant of use in the invention can befacilitated by the use of an insertion tool. For example, in someembodiments the lacrimal implants and/or the inserter tool may includefeatures or components that are found in U.S. Patent ApplicationPublication No. 2009/0104248, U.S. Patent Application Publication No.2010/0274204, U.S. Patent Application Publication No. 2009/0105749 andInternational Patent Application Publication No. WO 2011/066479, both ofwhich are incorporated herein by reference in their entirety.

Turning to FIG. 7, an exemplary insertion tool is shown engaged with animplant of the invention through meeting of pin 760 and insertion of thelacrimal implants into a lacrimal punctum. The lacrimal implants includethe exemplary embodiments disclosed above, variations thereof, or anysimilar structures.

3) Sustained Release Formulations

Conventional drug delivery involving frequent periodic dosing is notideal or practical in many instances. For example, with more toxicdrugs, conventional periodic dosing can result in unfavorably highinitial drug levels at the time of dosing, followed by low drug levelsbetween doses often times below levels of therapeutic value. Likewise,conventional periodic dosing may not be practical or therapeuticallyeffective in certain instances such as with pharmaceutical therapiestargeting areas of the inner eye or brain in need of treatment such asthe retina. Accordingly, in certain embodiments, the lacrimal implantfurther comprises one or more therapeutic agents within its structure.In certain embodiments, the therapeutic agent is dispersed throughoutthe device (e.g. providing a saturated or impregnated implant). In othercertain embodiments, the therapeutic agent is located at one or moredistinct locations or zones of the implant. In an exemplary embodiment,the therapeutic agent is located in a cavity of the device and thecomponent holding the therapeutic agent is referred to as a drug core.This drug core may comprise additional component such as an impermeablesheath to prevent migration of the therapeutic drug through the lacrimalimplant and/or provide direction for the drug migration.

In certain embodiments, in which the agent is dispersed throughout thedevice, the rate and location of release of the agent is controlled bycoating at least a component of the device with a material that isimpermeable to the drug. In an exemplary embodiment, essentially theentire device is coated with the material with the exception of one ormore gaps in the material through which the agent can elute into the eyeor surrounding tissue. An exemplary coating is a Parylene coating (See,US Patent Publication No. 2008/0181930, herein incorporated byreference).

In one embodiment, the lacrimal implant of the invention is configuredas a sustained release device, releasing the incorporated therapeuticagent in a therapeutically effective manner, e.g., at a rate thatprovides a therapeutically effective dosage for at least about 1 week, 2weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8, weeks, 9 weeks 10weeks, 11 weeks, or at least about 12 weeks or more. In an exemplaryembodiment, the lacrimal implant is configured to be retained by thepuncta for the duration of the intended controlled release of thetherapeutic agent. In various embodiments, the duration of the intendedcontrolled release of the therapeutic agent is at least about 1 week, 2weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8, weeks, 9 weeks 10weeks, 11 weeks, or at least about 12 weeks or more. In variousembodiments at least 95% of the implanted implants are retained for theduration of the intended controlled release of the therapeutic agent. Inan exemplary embodiment, the implant is retained by the puncta for alength of time to show therapeutic efficacy.

In an exemplary embodiment, the implant is formatted as a unit dosage ofthe therapeutic agent. In various embodiments, the implant is formattedas a unit dosage of an antiglaucoma agent. In an exemplary embodiment,the antiglaucoma agent is a prostaglandin.

Therapeutic Agent (Drug) Core

In an exemplary embodiment, the methods of the invention utilize animplant including a distinct therapeutic agent core or integrated drugor other agent disposed in at least one of the first member 305 or thesecond member 310 of the implant body, to provide a sustained release ofa therapeutic agent. For instance, the drug core or integrated drug orother agent disposed may be disposed in the cavity 458 of the lacrimalimplant 400 to provide a sustained drug or other therapeutic agentrelease.

An exemplary implant of use in the methods of the invention isconfigured to deliver a therapeutic agent to one or more of an eye,nasal passage or inner ear system. In various embodiments, the drug isdelivered systemically to the subject through the eye. A therapeuticagent core can comprise one or more therapeutic agents, and in someexamples, one or more matrix materials to provide sustained release ofthe drug or other agents.

In various embodiments, the therapeutic agent core is inserted intocavity 458.

In various examples, the distinct drug core or integrated drug or otheragent includes at least about 20 micrograms, at least about 40micrograms, at least about 45 micrograms, at least 80 micrograms, or atleast 95 micrograms of a drug (e.g., latanoprost), such as is furtherdiscussed in commonly-owned Butuner et al., U.S. Patent Publication No.2009/0280158, entitled “SUSTAINED RELEASE DELIVERY OF ACTIVE AGENTS TOTREAT GLAUCOMA AND OCULAR HYPERTENSION,” filed May 8, 2009, andcommonly-owned Butuner, U.S. Patent Publication No. US 2010/0209477,entitled “SUSTAINED RELEASE DELIVERY OF ONE OR MORE AGENTS,” filed Jan.22, 2010, both of which are incorporated by reference in their entirety,including their descriptions of drug or other agent concentration andformulations.

The drug core can comprise one or more biocompatible materials capableof providing a sustained release of the one or more drugs or agents. Thedrug core can comprise a matrix including a substantiallynon-biodegradable silicone matrix with dissolvable inclusions of thedrugs or agents located therein. The drug core can include otherstructures that provide sustained release of the drugs or agents, forexample a biodegradable matrix, a porous drug core, a liquid drug coreor a solid drug core. A matrix that includes the drugs or agents can beformed from either biodegradable or non-biodegradable polymers. In someexamples, a non-biodegradable drug core can include silicone, acrylates,polyethylenes, polyurethane, polyurethane, hydrogel, polyester (e.g.,DACRON™ from E.I. Du Pont de Nemours and Company, Wilmington, Del.),polypropylene, polytetrafluoroethylene (PTFE), expanded PTFE (ePTFE),polyether ether ketone (PEEK), nylon, extruded collagen, polymer foam,silicone rubber, polyethylene terephthalate, ultra high molecular weightpolyethylene, polycarbonate urethane, polyurethane, polyimides,stainless steel, nickel-titanium alloy (e.g., Nitinol), titanium,stainless steel, cobalt-chrome alloy (e.g., ELGILOY™ from ElginSpecialty Metals, Elgin, Ill.; CONICHROME™ from Carpenter Metals Corp.,Wyomissing, Pa.). In some examples, a biodegradable drug core cancomprise one or more biodegradable polymers, such as protein, hydrogel,polyglycolic acid (PGA), polylactic acid (PLA), poly(L-lactic acid)(PLLA), poly(L-glycolic acid) (PLGA), polyglycolide, poly-L-lactide,poly-D-lactide, poly(amino acids), polydioxanone, polycaprolactone,polygluconate, polylactic acid-polyethylene oxide copolymers, modifiedcellulose, collagen, polyorthoesters, polyhydroxybutyrate,polyanhydride, polyphosphoester, poly(alpha-hydroxy acid) andcombinations thereof. In some examples, the drug core can comprise ahydrogel polymer.

The therapeutic agent can be present in the device in a formulation witha pharmaceutically acceptable carrier, e.g., excipients, suspendingagents, diluents, fillers, salts, buffers, stabilizers, solubilizers,solvents, dispersion media, coatings, isotonic agents, and othermaterials known in the art. The pharmaceutical formulation optionallyincludes potentiators, complexing agents, targeting agents, stabilizingagents, cosolvents, pressurized gases, or solubilizing conjugates.

Exemplary excipients include sugars such as lactose, sucrose, mannitol,or sorbitol; cellulose preparations such as, maize starch, wheat starch,rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethylcellulose, sodium caroxymethylcellulose, and/orpolyvinylpyrrolidone (PVP). Preferred excipients include lactose,gelatin, sodium carboxymethyl cellulose, and low molecular weight starchproducts.

Exemplary suspending agents that can serve as valve lubricants inpressurized pack inhaler systems are desirable. Such agents includeoleic acid, simple carboxylic acid derivatives, and sorbitan trioleate.

Exemplary diluents include water, saline, phosphate-buffered citrate orsaline solution, and mucolytic preparations. Other diluents that can beconsidered include alcohol, propylene glycol, and ethanol; thesesolvents or diluents are more common in oral aerosol formulations.Physiologically acceptable diluents that have a tonicity and pHcompatible with the alveolar apparatus are desirable. Preferred diluentsinclude isotonic saline, phosphate buffered isotonic solutions whosetonicity have been adjusted with sodium chloride or sucrose or dextroseor mannitol.

Exemplary fillers include glycerin, propylene glycol, ethanol in liquidor fluid preparations. Suitable fillers for dry powder inhalationsystems include lactose, sucrose, dextrose, suitable amino acids, andderivatives of lactose. Preferred fillers include glycerin, propyleneglycol, lactose and certain amino acids.

Exemplary salts include those that are physiologically compatible andprovide the desired tonicity adjustment. Monovalent and divalent saltsof strong or weak acids are desirable. Preferred salts include sodiumchloride, sodium citrate, ascorbates, sodium phosphates.

Exemplary buffers include phosphate or citrate buffers or mixed buffersystems of low buffering capacity. Preferred buffers include phosphateor citrate buffers.

Table 1 shows exemplary drug insert silicones that may be used andassociated cure properties, according to embodiments of the presentinvention. The drug core insert matrix material can include a basepolymer comprising dimethyl siloxane, such as MED-4011, MED 6385 and MED6380, each of which is commercially available from NuSil. The basepolymer can be cured with a cure system such as a platinum-vinyl hydridecure system or a tin-alkoxy cure system, both commercially availablefrom NuSil. In many embodiments, the cure system may comprise a knowncure system commercially available for a known material, for example aknown platinum vinyl hydride cure system with known MED-4011. In aspecific embodiment shown in Table 1, 90 parts of MED-4011 can becombined with 10 parts of the crosslinker, such that the crosslinkercomprises 10% of the mixture. A mixture with MED-6385 may comprise 2.5%of the crosslinker, and mixtures of MED-6380 may comprise 2.5% or 5% ofthe crosslinker.

TABLE 1 Drug Insert Silicone Selections Crosslinker Material BasePolymer Cure System Percent MED-4011 Dimethyl siloxane Platinum vinyl 10% Silica filler hydride system material 10% MED-6385 Dimethylsiloxane Tin-Alkoxy 2.5% 2.5% Diatomaceous earth filler materialMED-6380 Dimethyl siloxane Tin-Alkoxy 2.5 to 5% without filler material

It has been determined according to the present invention that the curesystem and type of silicone material can affect the curing properties ofthe solid drug core insert, and may potentially affect the yield oftherapeutic agent from the drug core matrix material. In specificembodiments, curing of MED-4011 with the platinum vinyl hydride systemcan be inhibited with high concentrations of drug/prodrug, for exampleover 20% drug, such that a solid drug core may not be formed. Inspecific embodiments, curing of MED-6385 or MED 6380 with the tin alkoxysystem can be slightly inhibited with high concentrations, e.g. 20%, ofdrug/prodrug. This slight inhibition of curing can be compensated byincreasing the time or temperature of the curing process. For example,embodiments of the present invention can make drug cores comprising 40%drug and 60% MED-6385 with the tin alkoxy system using appropriate curetimes and temperatures. Similar results can be obtained with theMED-6380 system the tin-alkoxy system and an appropriate curing time ortemperature. Even with the excellent results for the tin alkoxy curesystem, it has been determined according to the present invention thatthere may be an upper limit, for example 50% drug/prodrug or more, atwhich the tin-alkoxy cure system may not produce a solid drug core. Inmany embodiments, the latanoprost or other intraocular pressure-reducingtherapeutic agent(s) in the solid drug core may be at least about 5%,for example a range from about 5% to 50%, and can be from about 20% toabout 40% by weight of the drug core.

In a specific embodiment, drug cores with two different concentrationsof Latanoprost are utilized in the method of the invention.

In one embodiment of the present methods an implant with a drug corewith 46 μg of Latanoprost was inserted into a lacrimal implant, SeeTable 2.

TABLE 2 Latanoprost Punctal Plug Delivery System (PPDS) Composition (46μg) L-PPDS, 46 μg Material Specific Formulation or ID Description withDMPC Latanoprost Chirogate International GMP grade, neat oil 46.0 μgEverlight Chemical Industrial Corporation Silicone NuSil MED-6385 (MAF970) Two part medical grade formulation Part A - proprietary silicone60.1 μg formulation Part B - stannous octoate 0.70 nL Crosslinker NuSilMED5-6382 (MAF 1289) Only crosslinker is used from kit 2.1 nLDimyristoyl Nippon Fine Chemical GMP grade, white solid 8.6 μgPhosphatidylcholine (DMPC) Tubing Polyimide Polyimide tube length(0.0155″ 0.95 mm inner diameter, with 0.0010″ wall - medical grade)Cyanoacrylate Loctite ® 4305 ™ Medical grade ethyl cyanoacrylate ~0.3 μgadhesive with photoinitiator

In another embodiment, a drug core with 95 μg of Latanoprost was madeand inserted into a lacrimal implant, see Table 3.

TABLE 3 Latanoprost Punctal Plug Delivery System (PPDS) Composition (95μg) L-PPDS, 95 μg Material Specific Formulation or ID Description withDMPC Latanoprost Everlight Chemical Industrial GMP grade, neat oil 95.0μg Corporation Silicone NuSil MED-6385 (MAF 970) Two part medical gradeformulation Part A - proprietary silicone 124.7 μg formulation Part B -stannous octoate 0.70 nL Crosslinker NuSil MED5-6382 (MAF 1289) Onlycrosslinker is used from kit 4.8 nL Dimyristoyl Nippon Fine Chemical GMPgrade, white solid 17.8 μg Phosphatidylcholine (DMPC) Tubing PolyimidePolyimide tube length (0.0220″ 0.95 mm inner diameter, with 0.0010″wall - medical grade) Cyanoacrylate Loctite ® 4305 ™ Medical grade ethylcyanoacrylate ~0.3 μg adhesive with photoinitiator

Further discussion of drug-releasing or other agent-releasing drug corescan be found in commonly-owned Utkhede et al., U.S. Patent PublicationNo. 2009/0104243, entitled “DRUG CORES. FOR SUSTAINED RELEASE OFTHERAPEUTIC AGENTS,” filed Sep. 5, 2008, which is herein incorporated byreference in its entirety.

Sheath Body

In certain embodiments, the implant of use in the methods of theinvention includes a therapeutic agent core which is encased in a sheathbody. The sheath body can comprise appropriate shapes and materials tocontrol the migration of latanoprost or other anti-glaucoma agents fromthe drug core. In some embodiments, the sheath body houses the drug coreand can fit snugly against the core. The sheath body is made from amaterial that is substantially impermeable to the therapeutic agent sothat the rate of migration of the agent may be largely controlled by theexposed surface area of the drug core that is not covered by the sheathbody. In certain embodiments, migration of the therapeutic agent throughthe sheath body can be about one tenth of the migration of thetherapeutic agent through the exposed surface of the drug core, or less,often being one hundredth or less. In other words, the migration of thetherapeutic agent through the sheath body is at least about an order ofmagnitude less that the migration of the therapeutic agent through theexposed surface of the drug core. Suitable sheath body materials includepolyimide, polyethylene terephthalate (hereinafter “PET”). The sheathbody has a thickness, as defined from the sheath surface adjacent thecore to the opposing sheath surface away from the core, from about0.00025″ to about 0.0015″. The total diameter of the sheath that extendsacross the core ranges from about 0.2 mm to about 1.2 mm. The core maybe formed by dip coating the core in the sheath material. Alternativelyor in combination, the sheath body can comprise a tube and the coreintroduced into the sheath, for example as a liquid or solid that can beslid, injected or extruded into the sheath body tube. The sheath bodycan also be dip coated around the core, for example dip coated around apre-formed core.

The sheath body can be provided with additional features to facilitateclinical use of the implant. For example, the sheath may receive a drugcore that is exchangeable while the implant body, retention structureand sheath body remain implanted in the subject. The sheath body isoften rigidly attached to the retention structure as described above,and the core is exchangeable while the retention structure retains thesheath body. In specific embodiments, the sheath body can be providedwith external protrusions that apply force to the sheath body whensqueezed and eject the core from the sheath body. Another drug core canthen be positioned in the sheath body. In many embodiments, the sheathbody or retention structure may have a distinguishing feature, forexample a distinguishing color, to show placement such that theplacement of the sheath body or retention structure in the canaliculusor other body tissue structure can be readily detected by the subject.The retention element or sheath body may comprise at least one mark toindicate the depth of placement in the canaliculus such that theretention element or sheath body can be positioned to a desired depth inthe canaliculus based on the at least one mark.

Formation of the Therapeutic Agent Cores

Those of skill in the art will be familiar with various methods usefulfor making the drug cores and inserting into the lacrimal implant tocomplete the present drug delivery system described as being of use inthe methods disclosed herein. Particular methods are described in theabove-identified patent documents, the disclosures of which areincorporated herein by reference in their entirety.

For example, drug cores as described above may be fabricated withdifferent cross sectional sizes of between about 0.006 inches and 0.025inches. Drug concentrations in the core may be about 5%, 10%, 20%, 30%,40% or 50% in a silicone matrix. These drug cores can be made with asyringe tube and cartridge assembly, mixing the therapeutic agent(s)with silicone, and injecting the mixture into a polyimide tube which iscut to desired lengths and sealed. The length of the drug cores can beapproximately 0.80 to 0.95 mm, or any length designed to fit within thecavity of the present lacrimal implants.

Syringe Tube and Cartridge Assembly: 1. Polyimide tubing of variousdiameters (for example 0.006 inches, 0.0125 inches and 0.025 inches) canbe cut to 15 cm length. 2. The polyimide tubes can be inserted into aSyringe Adapter. 3. The polyimide tube can be adhesive bonded into lueradapter (Loctite, low viscosity UV cure). 4. The end of the assembly canthen be trimmed. 5. The cartridge assembly can be cleaned usingdistilled water and then with methanol and dried in oven at 60 degreesC.

The therapeutic agent can be mixed with silicone. Therapeutic agent(s)may be provided as a 1% solution in methylacetate. The appropriateamount of solution can be placed into a dish and using a nitrogenstream, the solution can be evaporated until only the therapeuticagent(s) remains. The dish with the therapeutic agent(s) oil can beplaced under vacuum for 30 minutes. This therapeutic agent(s) can thenbe combined with silicone, with three different concentrations oftherapeutic agent(s) (5%, 10% and 20%) in silicone NuSil 6385 beinginjected into tubing of different diameters (0.006 in, 0.012 in and0.025 inches) to generate 3×3 matrixes. The tube can then beinjected: 1. The cartridge and polyimide tubes assembly can be insertedinto a 1 ml syringe. 2. One drop of catalyst (MED-6385 Curing Agent) canbe added in the syringe. 3. Excess catalyst can be forced out of thepolyimide tube with clean air. 4. The syringe can then be filled withsilicone drug matrix. 5. The tube can then be injected with drug matrixuntil the tube is filled or the syringe plunger becomes too difficult topush. 6. The distal end of the polyimide tube can be closed off andpressure can be maintained until the silicone begins to solidify. 7.Allow to cure at room temperature for 12 hours. 8. Place under vacuumfor 30 minutes. 9. The tube can then be place in the correct size trimfixture (prepared in house to hold different size tubing) and druginserts can be cut to length (0.80-0.95 mm).

In certain embodiments, the drug core formulations of Table 2 and 3 aremade using a cold extrusion method described in US Patent PublicationNo. 2009/0104243 entitled DRUG CORES FOR SUSTAINED RELEASE OFTHERAPEUTIC AGENTS. Filed Sep. 5, 2008, the entirety of which isincorporated herein by reference. See, Example 3.

In this instance, the silicone and latanoprost are prepared as describedabove. When latanoprost, which is in a liquid physical state at aboutroom temperature (22° C.), and thus is also in a liquid physical stateat human body temperature (37° C.), is used, the agent and the matrixmaterial can be mixed by techniques that bring about a high degree ofdispersion of the liquid latanoprost droplets in the matrix material inwhich it can be substantially insoluble. Mixing techniques shouldprovide for a dispersion of the droplet within the matrix material, suchthat when curing takes place, the liquid therapeutic agent is present asrelatively small, relatively homogeneously dispersed discrete dropletswithin the matrix of solid silicone material.

In this cold extrusion method, the mixture of latanoprost and siliconecan be injected into the tubing (e.g. sheath body) wherein the mixtureis at a subambient temperature. A syringe, for example a 1 ml syringe,can be connected to the syringe tube and cartridge assembly. A drop ofcatalyst appropriate for the silicone, for example MED-6385 curingagent, can be placed into the syringe and the syringe is then filledwith the uncured mixture of silicone and latanoprost. The mixture, i.e.,mixture of the uncured silicone and latanoprost still liquid enough toflow or pump, can be chilled to subambient temperatures. For example,the mixture can be chilled to temperatures of less than 20° C. Forexample, the mixtures can be chilled to 0° C., or to −25° C. In aparticular embodiment, the mixture is chilled to between about zero and5° C.

The polyimide tube is injected with the drug/matrix mixture until thetube is filled. The tube and associated apparatus can also be chilled tomaintain the subambient temperature of the mixture throughout theprocess of filling or injecting the sheath with the mixture. In variousembodiments, the polyimide tube, or sheath, is filled with the drugmatrix mixture under pressure, for example through use of a highpressure pump. For instance, the drug/matrix mixture, such as can beobtained in mixtures of latanoprost with MED-6385 Part A to whichamounts of catalyst Part B have been added, can be pumped into the tubeunder at least about 40 psi pressure. The tube can be filled at anysuitable rate, but preferably, at rates of less than about 0.5 linearcm/sec. Without wishing to be bound by a theory, it is believed thatfilling the tube relatively rapidly under a relatively high head ofpressure can reduce the degree of phase separation of the substantiallyimmiscible latanoprost oil and silicone monomer material, such that uponpolymerization (“curing”) to provide the final silicone polymericproduct, the latanoprost droplets are finely dispersed in the solidmatrix in which they are only slightly soluble.

Curing takes place in the presence of the catalyst (“Part B”) of theNuSil MED-6385, and can be carried out at temperatures of at least about40° C., at relative humidity (RH) of at least about 80%, or both. Curingcan be initiated directly after filling the tube and clamping the endsof the filled tube to prevent the formation of voids and loss of theprecursor material from the tube ends.

After curing, which can be complete in about 16-24 hours at 40° C. and80% RH, the clamps can be removed from the ends of the tubing, as thesilicone is fully set up. The tubing can then be cut into sections ofsuitable length for use as drug cores, for example, lengths of about 1mm.

When the extrusion is carried out at subambient temperatures, small andmore uniform inclusions of the therapeutic agent can result. Forexample, when the agent is latanoprost, a liquid at room temperature,extrusion at −5° C. provides significantly smaller and more uniforminclusion droplets. In an example, cold extrusion yielded a drug corecomprising a silicone matrix with latanoprost droplets of averagediameter of 6 μm, with a standard deviation of diameter of 2 μm. Incomparison, an extrusion carried out at room temperature yielded a drugcore comprising a silicone matrix with latanoprost droplets of averagediameter of 19 μm, with a standard deviation of droplet diameter of 19μm. It is apparent that the cold extrusion technique provides smaller,more uniform inclusions than does extrusion at room temperature. This inturn results in a more uniform concentration of drug throughout thecore, or the insert containing the core.

The final step in making the present lacrimal implants comprisesinserting the drug core, cut to an appropriate length and sealed on oneend, into the cavity of the lacrimal implant. This can be done manuallyor with the aid of a machine.

D) Release of Latanoprost or Other Intraocular Pressure-ReducingTherapeutic Agent(s) at Effective Levels

The rate of release of latanoprost or other intraocularpressure-reducing therapeutic agent(s) can be related to theconcentration of latanoprost or other intraocular pressure-reducingtherapeutic agent(s) dissolved in the drug core. In some embodiments,the drug core comprises non-therapeutic agents that are selected toprovide a desired solubility of the latanoprost or other intraocularpressure-reducing therapeutic agent(s) in the drug core. Thenon-therapeutic agent of the drug core can comprise polymers asdescribed herein, and additives. A polymer of the core can be selectedto provide the desired solubility of the latanoprost or otherintraocular pressure-reducing therapeutic agent(s) in the matrix. Forexample, the core can comprise hydrogel that may promote solubility ofhydrophilic treatment agent. In some embodiments, functional groups canbe added to the polymer to provide the desired solubility of thelatanoprost or other intraocular pressure-reducing therapeutic agent(s)in the matrix. For example, functional groups can be attached tosilicone polymer.

Additives may be used to control the concentration of latanoprost orother intraocular pressure-reducing therapeutic agent(s) by increasingor decreasing solubility of the latanoprost or other intraocularpressure-reducing therapeutic agent(s) in the drug core so as to controlthe release kinetics of the latanoprost or other intraocularpressure-reducing therapeutic agent(s). The solubility may be controlledby providing appropriate molecules or substances that increase ordecrease the content of latanoprost or other intraocularpressure-reducing therapeutic agent(s) in the matrix. The latanoprost orother intraocular pressure-reducing therapeutic agent(s) content may berelated to the hydrophobic or hydrophilic properties of the matrix andlatanoprost or other intraocular pressure-reducing therapeutic agent(s).For example, surfactants and salts can be added to the matrix and mayincrease the content of hydrophobic latanoprost in the matrix. Inaddition, oils and hydrophobic molecules can be added to the matrix andmay increase the solubility of hydrophobic treatment agent in thematrix.

Instead of or in addition to controlling the rate of migration based onthe concentration of latanoprost or other intraocular pressure-reducingtherapeutic agent(s) dissolved in the matrix, the surface area of thedrug core can also be controlled to attain the desired rate of drugmigration from the core to the target site. For example, a largerexposed surface area of the core will increase the rate of migration ofthe treatment agent from the drug core to the target site, and a smallerexposed surface area of the drug core will decrease the rate ofmigration of the latanoprost or other intraocular pressure-reducingtherapeutic agent(s) from the drug core to the target site. The exposedsurface area of the drug core can be increased in any number of ways,for example by any of castellation of the exposed surface, a poroussurface having exposed channels connected with the tear or tear film,indentation of the exposed surface, protrusion of the exposed surface.The exposed surface can be made porous by the addition of salts thatdissolve and leave a porous cavity once the salt dissolves. Hydrogelsmay also be used, and can swell in size to provide a larger exposedsurface area. Such hydrogels can also be made porous to further increasethe rate of migration of the latanoprost or other intraocularpressure-reducing therapeutic agent(s).

Further, an implant may be used that includes the ability to release twoor more drugs in combination, such as the structure disclosed in U.S.Pat. No. 4,281,654. For example, in the case of glaucoma treatment, itmay be desirable to treat a patient with multiple prostaglandins or aprostaglandin and a cholinergic agent or an adrenergic antagonist (betablocker), such as Alphagan®, or latanoprost and a carbonic anhydraseinhibitor.

In addition, drug impregnated meshes may be used such as those disclosedin U.S. Patent Publication No. 2002/0055701 or layering of biostablepolymers as described in U.S. Patent Publication No. 2005/0129731, thedisclosures of which are incorporated herein in their entirety. Certainpolymer processes may be used to incorporate latanoprost or otherintraocular pressure-reducing therapeutic agent(s) into the devices ofthe present invention; such as so-called “self-delivering drugs” orPolymerDrugs (Polymerix Corporation, Piscataway, N.J.) are designed todegrade only into therapeutically useful compounds and physiologicallyinert linker molecules, further detailed in U.S. Patent Publication No.2005/0048121, hereby incorporated by reference in its entirety. Suchdelivery polymers may be employed in the devices of the presentinvention to provide a release rate that is equal to the rate of polymererosion and degradation and is constant throughout the course oftherapy. Such delivery polymers may be used as device coatings or in theform of microspheres for a drug depot injectable (such as a reservoir ofthe present invention). A further polymer delivery technology may alsobe configured to the devices of the present invention such as thatdescribed in U.S. Patent Publication No. 2004/0170685, and technologiesavailable from Medivas (San Diego, Calif.).

In specific embodiments, the drug core matrix comprises a solidmaterial, for example silicone, that encapsulates inclusions of thelatanoprost or other intraocular pressure-reducing therapeutic agent(s).The drug comprises molecules which are very insoluble in water andslightly soluble in the encapsulating drug core matrix. The inclusionsencapsulated by the drug core can be micro-particles having dimensionsfrom about 1 micrometer to about 100 micrometers across. The druginclusions can comprise droplets of oil, for example latanoprost oil.The drug inclusions can dissolve into the solid drug core matrix andsubstantially saturate the drug core matrix with the drug, for exampledissolution of latanoprost oil into the solid drug core matrix. The drugdissolved in the drug core matrix is transported, often by diffusion,from the exposed surface of the drug core into the tear film. As thedrug core is substantially saturated with the drug, in many embodimentsthe rate limiting step of drug delivery is transport of the drug fromthe surface of the drug core matrix exposed to the tear film. As thedrug core matrix is substantially saturated with the drug, gradients indrug concentration within the matrix are minimal and do not contributesignificantly to the rate of drug delivery. As surface area of the drugcore exposed to the tear film is nearly constant, the rate of drugtransport from the drug core into the tear film can be substantiallyconstant. Naturally occurring surfactants may affect the solubility ofthe latanoprost or other intraocular pressure-reducing therapeuticagent(s) in water and molecular weight of the drug can affect transportof the drug from the solid matrix to the tear. In many embodiments, thelatanoprost or other intraocular pressure-reducing therapeutic agent(s)is nearly insoluble in water and has a solubility in water of about0.03% to 0.002% by weight and a molecular weight from about 400grams/mol. to about 1200 grams/mol.

In many embodiments the latanoprost or other intraocularpressure-reducing therapeutic agent(s) has a very low solubility inwater, for example from about 0.03% by weight to about 0.002% by weight,a molecular weight from about 400 grams per mole (g/mol) to about 1200g/mol, and is readily soluble in an organic solvent. Latanoprost is aliquid oil at room temperature, and has an aqueous solubility of 50micrograms/mL in water at 25 degrees C., or about 0.005% by weight and aM.W. of 432.6 g/mol.

Naturally occurring surfactants in the tear film, for example surfactantD and phospholipids, may affect transport of the drug dissolved in thesolid matrix from the core to the tear film. In some embodiments thedrug core can be configured in response to the surfactant in the tearfilm to provide sustained delivery of latanoprost or other intraocularpressure-reducing therapeutic agent(s) into the tear film at therapeuticlevels. For example, empirical data can be generated from a patientpopulation, for example 10 patients whose tears are collected andanalyzed for surfactant content. Elution profiles in the collected tearsfor a drug that is sparingly soluble in water can also be measured andcompared with elution profiles in buffer and surfactant such that an invitro model of tear surfactant is developed. An in vitro solution withsurfactant based on this empirical data can be used to adjust the drugcore in response to the surfactant of the tear film.

The drug cores may also be modified to utilize carrier vehicles such asnanoparticles or microparticles depending on the size of the molecule tobe delivered such as latent-reactive nanofiber compositions forcomposites and nanotextured surfaces (Innovative Surface Technologies,LLC, St. Paul, Minn.), nanostructured porous silicon, known asBioSilicon®, including micron sized particles, membranes, woven fiversor micromachined implant devices (pSividia, Limited, UK) and proteinnanocage systems that target selective cells to deliver a drug(Chimeracore).

In many embodiments, the drug insert comprises of a thin-walledpolyimide tube sheath with a drug core comprising latanoprost dispersedin Nusil 6385 (MAF 970), a medical grade solid silicone that serves asthe matrix for drug delivery. The distal end of the drug insert issealed with a cured film of solid Loctite 4305 medical grade adhesive.The drug insert may be placed within the bore of the punctal implant,the Loctite 4305 adhesive does not come into contact with either tissueor the tear film. The inner diameter of the drug insert can be 0.32 mm;and the length can be 0.95 mm. At least four latanoprost concentrationsin the finished drug product can be employed: Drug cores can comprise3.5, 7, 14 or 21 micrograms latanoprost, with percent by weightconcentrations of 5, 10, 20, or 30% respectively. Assuming an overallelution rate of approximately 100 ng/day, the drug core comprising 14micrograms of latanoprost is configured to deliver drug forapproximately at least 100 days, for example 120 days. The overallweight of the drug core, including latanoprost or other intraocularpressure-reducing therapeutic agent(s), can be about 70 micrograms. Theweight of the drug insert including the polyimide sleeve can beapproximately 100 micrograms. In an embodiment, the drug core cancomprise 46 micrograms of latanoprost, and in another embodiment, thedrug core can comprise 95 micrograms of latanoprost.

In many embodiments, the drug core may elute with an initial elevatedlevel of latanoprost or other intraocular pressure-reducing therapeuticagent(s) followed by substantially constant elution of the latanoprostor other intraocular pressure-reducing therapeutic agent(s). In manyinstances, an amount of latanoprost or other intraocularpressure-reducing therapeutic agent(s) released daily from the core maybe below the therapeutic levels and still provide a benefit to thepatient. An elevated level of eluted latanoprost or other intraocularpressure-reducing therapeutic agent(s) can result in a residual amountof latanoprost or other intraocular pressure-reducing therapeuticagent(s) or residual effect of the latanoprost or other intraocularpressure-reducing therapeutic agent(s) that is combined with asub-therapeutic amount of latanoprost or other intraocularpressure-reducing therapeutic agent(s) to provide relief to the patient.In embodiments where therapeutic level is about 80 ng per day, thedevice may deliver about 100 ng per day for an initial delivery period.The extra 20 ng delivered per day can have a beneficial effect whenlatanoprost or other intraocular pressure-reducing therapeutic agent(s)is released at levels below the therapeutic level, for example at 60 ngper day. As the amount of drug delivered can be precisely controlled, aninitial elevated dose may not result in complications or adverse eventsto the patient.

E) Clinical Use of the Drug Delivery System to Treat Glaucoma and/orOcular Hypertension

Ocular hypertension (OH) and primary open angle glaucoma (POAG) arecaused by a build-up of aqueous humor in the anterior chamber primarilydue to the eye's inability to properly drain aqueous fluid. The ciliarybody, situated at the root of the iris, continuously produces aqueoushumor. It flows into the anterior chamber and then drains via the anglebetween the cornea and iris through the trabecular meshwork and into achannel in the sclera. In the normal eye, the amount of aqueous humorbeing produced is equal to the amount that is draining out. However, inan eye in which this mechanism is compromised, intraocular pressure(IOP) rises. Elevated IOP represents a major risk factor forglaucomatous field loss. Results from several studies indicate thatearly intervention targeted at lowering intraocular pressure retards theprogression of optic nerve damage and loss of visual fields that lead todecreased vision and blindness.

As described above, first line treatment for treating OAG and/or OH isthe use of eye drops, such as Xalatan. However, numerous studies havebeen published showing high noncompliance by patients using eye dropsfor treatment of various ocular disorders. One study showed only 64% ofpatients used the eye drops as directed (Winfield A J, et al. A study ofthe causes of non-compliance by patients prescribed eyedrops. Br JOphthalmol. 1990 August; 74(8):477-80). Another study showed that 41% ofpatients using eye drops for glaucoma missed six or more doses over a30-day period (Norell S E, Granstrom P A. Self-medication withpilocarpine among outpatients in a glaucoma clinic. Br J Ophthalmol.1980 February; 64(2):137-41).

In certain embodiments, the invention described herein provides methodsto treat glaucoma that avoid the problem of noncompliance associatedwith eye drop administration. In some embodiments, the methods of theinvention reduce patient noncompliance significantly compared to eyedrop administration, e.g., by at least about 10%, at least about 20%, atleast about 30%, at least about 40%, at least about 50%, at least about60%, at least about 70%, at least about 80%, or at least about 90%. Insome embodiments, overall patient noncompliance with the methodsdescribed herein is about 5%, about 10%, about 15%, about 20%, or about25%.

Patient noncompliance may occur if an implant of the invention isintentionally removed by a patient or if the patient does not seekreinsertion of the implant after such implant has been unintentionallylost from the punctum of the patient. Patient compliance is consideredto be met if the implant is intentionally removed and the patient seeksreinsertion within less than about 48 hours. Patient compliance is alsoconsidered to be met if the implant is intentionally removed and thepatient seeks reinsertion within less than about 24 hours of removal orloss of the implant.

Implicit in the methods to treat OAG and/or OH to avoid patientnon-compliance is the comparable efficacy of the present drug deliverysystem comprising lacrimal implants to the use of eye drops. Lacrimalimplants to treat ocular disease have been in development for many yearsby the applicants and others with limited success. However, applicantsdemonstrate for the first time herein a clinically meaningful reductionin IOP over the treatment period (e.g. between 4 weeks and 12 weeks)using the present lacrimal implants to administer latanoprost.

In certain embodiments, the invention described herein provides methodsto treat glaucoma, elevated intraocular pressure, andglaucoma-associated elevated intraocular pressure with a therapeuticagent. Examples of glaucoma treatable according to the present inventioninclude primary open angle glaucoma, normal intraocular tensionglaucoma, hypersecretion glaucoma, ocular hypertension, acuteangle-closure glaucoma, chronic closed angle glaucoma,combined-mechanism glaucoma, corticosteroid glaucoma, amyloid glaucoma,neovascular glaucoma, malignant glaucoma, capsular glaucoma, plateauiris syndrome and the like.

In one embodiment, the present disclosure provides methods of treating apatient with open angle glaucoma (OAG) and/or ocular hypertension (OH)in an eye. In a further embodiment, the present disclosure providesmethods of treating a patient with Open Angle Glaucoma (OAG) or OcularHypertension (OH) in an eye by reducing intraocular pressure (IOP) inthe eye.

In certain embodiments the treatment period is at least four (4) weeks,and can be up to twelve (12) week or longer, wherein the therapeuticagent is released in a therapeutically effective dose from a lacrimalimplant on a sustained basis over the treatment period.

In one embodiment, the implants and methods of the invention provide a90-day course of treatment. In other embodiments, the implants andmethods of the invention provide a 60-day course of treatment. In stillother embodiments, the implants and methods of the invention provide a45-day course of treatment. In still other embodiments, the implants andmethods of the invention provide a 30-day course of treatment, dependingupon the disease to be treated and the therapeutic agent to bedelivered. Other embodiments include four weeks, five weeks, six weeks,seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks, or twelveweeks of treatment.

In certain embodiments, the methods comprise reducing the intraocularpressure (IOP) during the treatment period. In one embodiment, reductionin intraocular pressure (IOP) is between about 10% and 24% from baselineover the treatment period. In particular embodiments, the percentagereduction or decrease in intraocular pressure (IOP) is approximately23%, approximately 22%, approximately 21%, or approximately 20% frombaseline. In other particular embodiments, the present methods result ina percentage reduction or decrease in intraocular pressure (IOP) of atleast 24%, at least 23%, at least 22%, at least 21%, at least 20%, atleast 15%, or at least 10% from baseline.

In certain embodiments, the methods of the invention result in areduction in intraocular pressure from baseline over a treatment periodof about 4, mm Hg, about 5 mm Hg, about 6 mm Hg, or about 7 mm Hg. Incertain embodiments, the methods of the invention result in a reductionin intraocular pressure from baseline of at least 4 mm Hg, at least 5 mmHg, at least 6 mm Hg, or at least 7 mm Hg. In some embodiments,intraocular pressure is reduced to less than or equal to 24 mm Hg, lessthan or equal to 23 mm Hg, less than or equal to 22 mm Hg, less than orequal to 21 mm Hg, less than or equal to 20 mm Hg, less than or equal to19 mm Hg, less than or equal to 18 mm Hg, or less than or equal to 17 mmHg, or less than or equal to 16 mm Hg, less than or equal to 15 mm Hg,less than or equal to 14 mm Hg, or less than or equal to 13 mm Hg.

In one embodiment, the invention provides a method of treating glaucomaand/or ocular hypertension with a punctal plug delivering a therapeuticagent effective against these conditions in a sustained release manner.The release occurs at a rate and in an amount sufficient to betherapeutically useful. In various embodiments, the therapeutic agent isa prostaglandin, e.g., latanoprost.

In an exemplary embodiment, the condition treated is primary open-angleglaucoma (POAG) and ocular hypertension (OH) with a punctual plug of theinvention in which a sustained release formulation of a prostaglandinderivative is provided. In this method one to four punctual plugs may beinserted per patient. Exemplary punctal plugs are formulated with fromabout 40 μg to about 115 μg of prostaglandin. In various embodiments,the prostaglandin is latanoprost. In various embodiments, the plugs areformulated with either 46 μg or 95 μg of latanoprost (See, Tables 2 and3) so that a dosage which is a member selected from 46 μg, 92 μg, 95 μg,141 μg or 190 μg is administered to each eye. In one embodiment 141 μgof latanoprost was administered to an individual eye. In anotherembodiment, 190 μg of latanoprost was administered to an individual eye.In another embodiment, 95 μg of latanoprost was administered to anindividual eye. A patient may have the same amount of latanoprostadministered to each eye or the patient may have a different amountadministered to each eye.

The implants described herein may be inserted into the superior (upper)punctum, the inferior (lower) punctum, or both, and may be inserted intoone or both eyes of the subject. Without wishing to be bound by atheory, the data presented in the figures and examples appear todemonstrate that the placement and configuration of the lacrimalimplants may contribute to the reduction of IOP over the treatmentperiod. In previously published studies, the lacrimal implants were onlyinserted into the lower punctum, and those studies, despite doseescalation (FIG. 16) and with a constant elution of drug over thetreatment period (FIG. 17) were unable to show significant reduction inIOP over the treatment period. See Example 2. Thus, in certainembodiments at least the upper punctum is inserted with a presentlacrimal implant. Surprisingly though, this lacrimal implant need notcomprise a therapeutic agent (See Example 6 and FIGS. 19 and 27). Inthis instance a blank lacrimal implant is inserted into the upperpunctum and a lacrimal implant comprising a therapeutic agent (e.g. 95μg of latanoprost) is inserted into the lower punctum. Thisconfiguration demonstrated a mean reduction in IOP from baseline of 5.17mm Hg at week twelve (FIG. 23 and Table 8), while previous studies withno lacrimal implant in the upper punctum and the same concentration oflatanoprost in the lower puntum lacrimal implant demonstrated only areduction of less than about 4.0 mm Hg from baseline at week 2 (FIG.16).

In certain embodiments, the method for treating OAG and/or OH comprisesinserting a lacrimal implant into at least the upper punctum. In oneembodiment, the lacrimal implant comprises a therapeutic agent (e.g.latanoprost). In another embodiment, the lacrimal implant does notcomprise a therapeutic agent for treating OAG and/or OH. In thisinstance, a lacrimal implant is inserted into the lower punctumcomprising a therapeutic agent (e.g. latanoprost).

Thus, the present methods comprise inserting at least a lacrimal implantinto an upper punctum wherein a number of different configurations arecontemplated resulting in significant reduction of IOP over thetreatment period. In one embodiment, the method for treating OAG and/orOH comprises inserting a lacrimal implant into the upper punctumcomprising a therapeutic agent and inserting a lacrimal implant into thelower punctum comprising a therapeutic agent. In another embodiment, themethod of treating OAG and/or OH comprises inserting a lacrimal implantinto the upper punctum that does not comprise a therapeutic agent forlowering IOP and inserting a lacrimal implant into the lower punctumthat comprises a therapeutic agent for treating OAG and/or OH. In yetanother embodiment, the present method for treating OAG and/or OHcomprises inserting a lacrimal implant into the upper punctum comprisinga therapeutic agent wherein no lacrimal implant is inserted into thelower punctum. In each of the above embodiments, reference to an upperand lower punctum is referring to the same eye. Each eye may have thesame configuration of lacrimal implant inserted or different; each eyeis treated separately for OAG and/or OH.

In a particular embodiment, the method of treating OAG and/or OH in aneye comprises providing a first lacrimal implant comprising a sustainedrelease formulation of a therapeutic agent for treating OAG or OH;providing a second lacrimal implant that does not comprise thetherapeutic agent; and inserting the first and second lacrimal implantthrough an upper and lower punctum into a lacrimal canaliculus of thesame eye wherein the therapeutic agent is released in a therapeuticallyeffective dose from the first lacrimal implant on a sustained basis overat least four (4) weeks. In one aspect, the therapeutic agent islatanoprost. In another aspect, the dose of latanoprost administered tothe eye is about 95 μg. In yet another aspect, the therapeutic agent isreleased in a therapeutically effective dose from the first lacrimalimplant on a sustained basis over at least twelve (12) weeks. In thisparticular embodiment, it was surprisingly found that the IOP wasreduced by about 5.0 mm Hg at week 4 and about at least 4.0 mm Hg atweek 12.

In another particular embodiment, the method of treating OAG and/or OHin an eye comprises providing a lacrimal implant comprising a sustainedrelease formulation of a therapeutic agent for treating OAG or OH; andinserting the lacrimal implant through an upper punctum into a lacrimalcanaliculus of the eye wherein the therapeutic agent is released in atherapeutically effective dose from the first lacrimal implant on asustained basis over at least four (4) weeks. In one aspect, thetherapeutic agent is latanoprost. In another aspect, the dose oflatanoprost administered to the eye is about 95 μg. In yet anotheraspect, the therapeutic agent is released in a therapeutically effectivedose from the first lacrimal implant on a sustained basis over at leasttwelve (12) weeks. In this particular embodiment, it was surprisinglyfound that the IOP was reduced by about at least 4.0 mm Hg at week 4 andabout at least 4.0 mm Hg at week 12.

In some embodiments, the therapeutic agent is released to the eye over asustained period of time. In an embodiment, the sustained period of timeis at least about 28 days, about 45 days, about 60 days or at leastabout 90 days. In some embodiments, the method comprises insertingthrough a punctum an implant having a body and a drug core so that thedrug core is retained near the punctum. In some embodiments, the methodcomprises inserting through a punctum an implant having a body dispersedthroughout with a therapeutic agent. In some embodiments, an exposedsurface of the drug core or agent dispersed body located near theproximal end of the implant contacts the tear or tear film fluid and thelatanoprost or other intraocular pressure-reducing therapeutic agent(s)migrates from the exposed surface to the eye over a sustained period oftime while the drug core and body is at least partially retained withinthe punctum. In an exemplary embodiment, a method of treating an eyewith latanoprost or other intraocular pressure-reducing therapeuticagent(s) is provided, the method comprising inserting through a punctuminto a canalicular lumen an implant having an optional retentionstructure so that the implant body is anchored to a wall of the lumen bythe retention structure. The implant releases effective amounts oflatanoprost or other intraocular pressure-reducing therapeutic agent(s)from a drug core or other agent supply into a tear or tear film fluid ofthe eye. In some embodiments, the drug core may be removed from theretention structure while the retention structure remains anchoredwithin the lumen. A replacement drug core can then be attached to theretention structure while the retention structure remains anchored. Atleast one exposed surface of the replacement drug core releaseslatanoprost or other intraocular pressure-reducing therapeutic agent(s)at therapeutic levels over a sustained period.

A replacement implant, or in other embodiments, a replacement drug corewhich can in some embodiments be attached to or include its ownretention structure, can be attached to the retention structureapproximately every 30 days, approximately every 60 days orapproximately every 90 days to result in continuous release of the drugto the eye for a period of time of approximately 180 days, approximately270 days, approximately 360 days, approximately 450 days, approximately540 days, approximately 630 days, approximately 720 days, approximately810 days or approximately 900 days. In some embodiments, a replacementimplant can be inserted into the punctum approximately every 30 days,approximately every 60 days or approximately every 90 days to achieverelease of the drug to the eye for extended periods of time, includingup to about 180 days, about 270 days, about 360 days, about 450 days,about 540 days, about 630 days, about 720 days, about 810 days or about900 days.

In other embodiments, a method for treating an eye with latanoprost orother intraocular pressure-reducing therapeutic agent(s) is provided,the method comprising inserting a drug core or other implant body atleast partially into at least one punctum of the eye. The drug core mayor may not be associated with a separate implant body structure. Thedrug core or agent-impregnated implant body provides sustained releasedelivery of latanoprost or other intraocular pressure-reducingtherapeutic agent(s) at therapeutic levels. In some embodiments, thesustained release delivery of latanoprost or other intraocularpressure-reducing therapeutic agent(s) continues for up to 90 days.

In exemplary embodiments, a method for treating an eye with latanoprostor other intraocular pressure-reducing therapeutic agent(s) is provided,the method comprising inserting a distal end of an implant into at leastone punctum and into at least one lacrimal canaliculus of the eye. Insome embodiment, a retention structure of the implant is fitted so as toinhibit expulsion of the implant. The expansion of the retentionstructure can help to occlude a flow of tear fluid through the punctum.In some embodiments, the implant is configured such that, whenimplanted, at least 45 degree angled intersection exists between a firstaxis, defined by a proximal end of the implant, and a second axis,defined by the distal end of the implant, to inhibit expulsion of theimplant. Latanoprost or other intraocular pressure-reducing therapeuticagent(s) is delivered from a proximal end of the implant to the tearfluid adjacent the eye. Delivery of the latanoprost or other intraocularpressure-reducing therapeutic agent(s) is inhibited distally of theproximal end.

The methods of the invention provide sustained release of latanoprost orother intraocular pressure-reducing therapeutic agent(s). In someembodiments, the active agent is released from the implant for at leastfour weeks, at least five weeks, at least six weeks, at least sevenweeks, at least eight weeks, at least nine weeks, at least ten weeks, atleast eleven weeks, at least twelve weeks, at least thirteen weeks, atleast fourteen weeks, at least fifteen weeks, or at least sixteen weeks.In some embodiments, the therapeutic agent is latanoprost. In anembodiment, the latanoprost or other intraocular pressure-reducingtherapeutic agent(s) is released for at least twelve weeks. In anexemplary embodiment, the methods of treatment according to the presentinvention comprise an adjunctive therapy with a latanoprost-deliveringeye drop solution, for example, Xalatan®.

The amount of latanoprost or other intraocular pressure-reducingtherapeutic agent(s) associated with the implant may vary depending onthe desired therapeutic benefit and the time during which the device isintended to deliver the therapy. Since the devices of the presentinvention present a variety of shapes, sizes and delivery mechanisms,the amount of drug associated with the device will depend on theparticular disease or condition to be treated, and the dosage andduration that is desired to achieve the therapeutic effect. Generally,the amount of latanoprost or other intraocular pressure-reducingtherapeutic agent(s) is at least the amount of drug that, upon releasefrom the device, is effective to achieve the desired physiological orpharmacological local or systemic effects.

Certain embodiments of the implants of the present invention can beconfigured to provide, in combination with each other or separately,delivery of latanoprost or other intraocular pressure-reducingtherapeutic agent(s) at daily rates that are greater than or equivalentto the therapeutically effective drop form of treatment. Otherembodiments of the implants of the present invention can be configuredto provide, in combination with each other or separately, delivery oflatanoprost or other intraocular pressure-reducing therapeutic agent(s)at daily rates that enable comparable clinical outcomes to that of dailyadministered eye drops. Other embodiments of the implants of the presentinvention can be configured to provide delivery of latanoprost or otherintraocular pressure-reducing therapeutic agent(s) at daily rates thatexceed the therapeutically effective drop form of treatment.

For comparison purposes, standard treatment, i.e., the recommended dailytotal dose, with drops, such as Xalatan® drops, delivers about 1.5micrograms of latanoprost to the eye all at once, assuming a 35microliter drop volume. In embodiments of the present invention, thesustained release of at least 1.5 micrograms of latanoprost per day canbe administered. For example, in an embodiment, a sustained releaseophthalmic drug delivery system is configured to release, on a sustainedbasis over the course of 24 hours to the eye, a total amount oflatanoprost from a combination of a first lacrimal implant, located in alower punctum of the eye, and a second lacrimal implant, located in anupper punctum of the same eye, that is greater than or equal to therecommended daily total dose of latanoprost that is in Xalatan® drops(i.e., eye drop form). In other embodiments, at least two times therecommended daily total dose of latanoprost that is in Xalatan® dropsmay be release by a combination of the first lacrimal implant and thesecond lacrimal implant that are in the lower punctum and the upperpunctum, respectively, of the same eye. In an embodiment, both eyes ofthe patient may be treated with two lacrimal implants at the same time.

Methods of inserting and removing the implant are known to those ofskill in the art. For instance, tools for insertion andremoval/extraction of implants are described in U.S. Patent PublicationNo. 2009/0105749 (filed Sep. 5, 2008 and entitled Insertion andExtraction Tools for Lacrimal Implants), the disclosure of which isincorporated herein in its entirety. Generally, for placement, the sizeof a punctal implant to be used may be determined by using suitablemagnification or, if provided, using a sizing tool that accompanies thepunctal implant. The patient's punctum may be dilated if necessary tofit the punctal implant. A drop of lubricant may be applied if necessaryto facilitate placement of the implant into the punctum. Using anappropriate placement instrument, the implant may be inserted into thesuperior or inferior punctum of the eye. After placement, the cap of theimplant may be visible. This process may be repeated for the patient'sother eye. For removal of the implant, small surgical forceps may beused to securely grasp the implant at the tube section below the cap.Using a gentle tugging motion the implant may be gently retrieved.

F) Kits

The present invention also provides methods that utilize kits that, inan exemplary embodiment, include one, two, three or four implants of usein the methods of the invention. In an exemplary embodiment, theimplants are sterilized. In various embodiments, there is also providedan insertion tool. An exemplary insertion tool of use in this embodimentis set forth herein. In various embodiments, at least one implant isengaged with the insertion tool by engaging the pin of the tool (760)with the bore of the implant (385). In various embodiments, the tool issterilized. In an exemplary embodiment, the elements of the kit arepackaged together with one or more of a set of instructions forinstalling the implant in the punctum, a topical anesthetic, anadministration device for the topical anesthetic or another component ofuse in installing the implant in the punctum.

G) Specific Embodiments

E1. A method of treating a patient with Open Angle Glaucoma (OAG) orOcular Hypertension (OH) in an eye, comprising: providing a unit dosageof about 95 μg of latanoprost to an eye over a treatment period, whereinthe latanoprost is administered from a lacrimal implant comprising asustained release formulation of the 95 ug of latanoprost and thelatanoprost is released in a therapeutically effective dose from thelacrimal implant over the treatment period, with the proviso that thelacrimal implant is inserted into an upper punctum of the eye and alower punctum of the eye is open or has inserted a blank lacrimalimplant that does not comprise latanoprost.

E2. A method of treating a patient with Open Angle Glaucoma (OAG) orOcular Hypertension (OH) in an eye, comprising: providing a unit dosageof about 95 μg of latanoprost to an eye over a treatment period, whereinthe latanoprost is administered from a lacrimal implant comprising asustained release formulation of the 95 μg of latanoprost and thelatanoprost is released in a therapeutically effective dose from thelacrimal implant over the treatment period, with the proviso that thelacrimal implant is inserted into a lower punctum and a blank lacrimalimplant that does not comprise latanoprost is inserted in an upperpunctum.

E3. A method of treating a patient with Open Angle Glaucoma (OAG) orOcular Hypertension (OH) in an eye by reducing intraocular pressure(IOP) in the eye, comprising: providing a unit dosage of about 95 μg oflatanoprost to an eye over a treatment period of at least 4 weeks,wherein the latanoprost is administered from a lacrimal implantcomprising a sustained release formulation of the 95 μg of latanoprostand the latanoprost is released in a therapeutically effective dose fromthe lacrimal implant over the treatment period, wherein the IOP isreduced by at least 4 mm Hg from a baseline at week 4.

E4. A method of treating a patient with Open Angle Glaucoma (OAG) orOcular Hypertension (OH) in an eye by reducing intraocular pressure(IOP) in the eye, comprising: providing a unit dosage of about 95 μg oflatanoprost to an eye over a treatment period of at least 8 weeks,wherein the latanoprost is administered from a lacrimal implantcomprising a sustained release formulation of the 95 μg of latanoprostand the latanoprost is released in a therapeutically effective dose fromthe lacrimal implant over the treatment period, wherein the IOP isreduced by at least 4 mm Hg from a baseline at week 8.

E5. A method of treating a patient with Open Angle Glaucoma (OAG) orOcular Hypertension (OH) in an eye by reducing intraocular pressure(IOP) in the eye, comprising: providing a unit dosage of about 95 μg oflatanoprost to an eye over a treatment period of at least 12 weeks,wherein the latanoprost is administered from a lacrimal implantcomprising a sustained release formulation of the 95 μg of latanoprostand the latanoprost is released in a therapeutically effective dose fromthe lacrimal implant over the treatment period, wherein the IOP isreduced by at least 4 mm Hg from a baseline at week 12.

E6. A method of treating a patient with Open Angle Glaucoma (OAG) orOcular Hypertension (OH) in an eye by reducing intraocular pressure(IOP) in the eye, comprising: providing a unit dosage of about between140 and 200 μg of latanoprost to an eye over a treatment period of atleast 4 weeks, wherein the latanoprost is administered from a lacrimalimplant comprising a sustained release formulation of the latanoprostand the latanoprost is released in a therapeutically effective dose fromthe lacrimal implant over the treatment period, wherein the IOP isreduced by at least 5 mm Hg from a baseline at week 4.

E7. A method of treating a patient with Open Angle Glaucoma (OAG) orOcular Hypertension (OH) in an eye by reducing intraocular pressure(IOP) in the eye, comprising: providing a unit dosage of about between140 and 200 μg of latanoprost to an eye over a treatment period of atleast 8 weeks, wherein the latanoprost is administered from a lacrimalimplant comprising a sustained release formulation of the latanoprostand the latanoprost is released in a therapeutically effective dose fromthe lacrimal implant over the treatment period, wherein the IOP isreduced by at least 5 mm Hg from a baseline at week 8.

E8. A method of treating a patient with Open Angle Glaucoma (OAG) orOcular Hypertension (OH) in an eye by reducing intraocular pressure(IOP) in the eye, comprising: providing a unit dosage of about between140 and 200 μg of latanoprost to an eye over a treatment period of atleast 12 weeks, wherein the latanoprost is administered from a lacrimalimplant comprising a sustained release formulation of the latanoprostand the latanoprost is released in a therapeutically effective dose fromthe lacrimal implant over the treatment period, wherein the IOP isreduced by at least 5 mm Hg from a baseline at week 12.

E9. A method of treating a patient with Open Angle Glaucoma (OAG) orOcular Hypertension (OH) in an eye by reducing intraocular pressure(IOP) in the eye, comprising: providing a unit dosage of about 190 μg oflatanoprost to an eye over a treatment period of at least 4 weeks,wherein the latanoprost is administered from a lacrimal implantcomprising a sustained release formulation of the latanoprost and thelatanoprost is released in a therapeutically effective dose from thelacrimal implant over the treatment period, wherein the IOP is reducedby at least 5 mm Hg from a baseline at week 4.

E10. A method of treating a patient with Open Angle Glaucoma (OAG) orOcular Hypertension (OH) in an eye by reducing intraocular pressure(IOP) in the eye, comprising: providing a unit dosage of about 190 μg oflatanoprost to an eye over a treatment period of at least 8 weeks,wherein the latanoprost is administered from a lacrimal implantcomprising a sustained release formulation of the latanoprost and thelatanoprost is released in a therapeutically effective dose from thelacrimal implant over the treatment period, wherein the IOP is reducedby at least 5 mm Hg from a baseline at week 8.

E11. A method of treating a patient with Open Angle Glaucoma (OAG) orOcular Hypertension (OH) in an eye by reducing intraocular pressure(IOP) in the eye, comprising: providing a unit dosage of about 190 μg oflatanoprost to an eye over a treatment period of at least 12 weeks,wherein the latanoprost is administered from a lacrimal implantcomprising a sustained release formulation of the latanoprost and thelatanoprost is released in a therapeutically effective dose from thelacrimal implant over the treatment period, wherein the IOP is reducedby at least 4 mm Hg from a baseline at week 12.

E12. A method of treating a patient with Open Angle Glaucoma (OAG) orOcular Hypertension (OH) in an eye by reducing intraocular pressure(IOP) in the eye, comprising: providing a unit dosage of about 141 μg oflatanoprost to an eye over a treatment period of at least 8 weeks,wherein the latanoprost is administered from a lacrimal implantcomprising a sustained release formulation of the latanoprost and thelatanoprost is released in a therapeutically effective dose from thelacrimal implant over the treatment period, wherein the IOP is reducedby at least 5 mm Hg from a baseline at week 8.

E13. A method of treating a patient with Open Angle Glaucoma (OAG) orOcular Hypertension (OH) in an eye, comprising: (a) providing a firstlacrimal implant comprising a sustained release formulation of atherapeutic agent for treating OAG or OH; (b) providing a secondlacrimal implant that does not comprise the therapeutic agent; and (c)inserting the first and second lacrimal implant through an upper andlower punctum into a lacrimal canaliculus of the same eye wherein thetherapeutic agent is released in a therapeutically effective dose fromthe first lacrimal implant on a sustained basis over at least four (4)weeks.

E14. A method of treating a patient with Open Angle Glaucoma (OAG) orOcular Hypertension (OH) in an eye, comprising: (a) providing a firstlacrimal implant comprising a sustained release formulation of atherapeutic agent for treating OAG or OH; (b) providing a secondlacrimal implant that does not comprise the therapeutic agent; and (c)inserting the first and second lacrimal implant through an upper andlower punctum into a lacrimal canaliculus of the same eye wherein thetherapeutic agent is released in a therapeutically effective dose fromthe first lacrimal implant on a sustained basis over at least eight (8)weeks.

E15. A method of treating a patient with Open Angle Glaucoma (OAG) orOcular Hypertension (OH) in an eye, comprising: (a) providing a firstlacrimal implant comprising a sustained release formulation of atherapeutic agent for treating OAG or OH; (b) providing a secondlacrimal implant that does not comprise the therapeutic agent; (c)inserting the first and second lacrimal implant through an upper andlower punctum into a lacrimal canaliculus of the same eye; and (d)releasing the therapeutic agent from the first lacrimal implant as atherapeutically effective dose on a sustained basis over at least twelve(12) weeks.

E16. A method of treating a patient with Open Angle Glaucoma (OAG) orOcular Hypertension (OH) in an eye by reducing intraocular pressure(IOP) in the eye, comprising: (a) measuring the IOP of the patient toobtain a baseline IOP before treatment; (b) providing a therapeuticagent for treating OAG or OH as a sustained release formulation; (c)delivering the sustained release formulation to the eye using a lacrimalimplant comprising the sustained release formulation; and (d) releasingthe therapeutic agent to the eye on a sustained basis over at least 8weeks wherein the IOP is reduced by at least 4 mmHg from baseline atweek 8.

E17. A method of treating a patient with Open Angle Glaucoma (OAG) orOcular Hypertension (OH) in an eye by reducing intraocular pressure(IOP) in the eye, comprising: (a) measuring the IOP of the patient toobtain a baseline IOP before treatment; (b) providing a therapeuticagent for treating OAG or OH as a sustained release formulation; (c)delivering the sustained release formulation to the eye using a lacrimalimplant comprising the sustained release formulation; and (d) releasingthe therapeutic agent to the eye on a sustained basis over at least 12weeks wherein the IOP is reduced by at least 4.0 mmHg from baseline atweek 12.

E18. A method of treating a patient with Open Angle Glaucoma (OAG) orOcular Hypertension (OH) in an eye by reducing intraocular pressure(IOP) in the eye, comprising: (a) measuring the IOP of the patient toobtain a baseline IOP before treatment; (b) providing a therapeuticagent for treating OAG or OH as a sustained release formulation; (c)delivering the sustained release formulation to the eye using a lacrimalimplant comprising the sustained release formulation; and (d) releasingthe therapeutic agent to the eye on a sustained basis over at least 12weeks wherein the IOP is reduced by at least 5.0 mmHg from baseline atweek 12.

E19. A lacrimal implant comprising a unit dosage of about 95 μg oflatanoprost for use in the treatment of Open Angle Glaucoma (OAG) orOcular Hypertension (OH) in an eye, wherein the latanoprost isadministered from the lacrimal implant comprising a sustained releaseformulation of the 95 ug of latanoprost and the latanoprost is releasedin a therapeutically effective dose from the lacrimal implant over atreatment period, with the proviso that the lacrimal implant is insertedinto an upper punctum of the eye and a lower punctum of the eye is openor has inserted a blank lacrimal implant that does not compriselatanoprost.

E20. A lacrimal implant comprising a unit dosage of about 95 μg oflatanoprost for use in the treatment of Open Angle Glaucoma (OAG) orOcular Hypertension (OH) in an eye, wherein the latanoprost isadministered from the lacrimal implant comprising a sustained releaseformulation of the 95 μg of latanoprost and the latanoprost is releasedin a therapeutically effective dose from the lacrimal implant over thetreatment period, with the proviso that the lacrimal implant is insertedinto a lower punctum and a blank lacrimal implant that does not compriselatanoprost is inserted in an upper punctum.

E21. A lacrimal implant comprising a unit dosage of about 95 μg oflatanoprost for use in the treatment of Open Angle Glaucoma (OAG) orOcular Hypertension (OH) in an eye by reducing intraocular pressure(IOP) in the eye, wherein the latanoprost is administered from alacrimal implant comprising a sustained release formulation of the 95 μgof latanoprost and the latanoprost is released in a therapeuticallyeffective dose from the lacrimal implant over a treatment period of atleast 4 weeks, wherein the IOP is reduced by at least 4 mm Hg from abaseline at week 4.

E22. A lacrimal implant comprising a unit dosage of about 95 μg oflatanoprost for use in the treatment of Open Angle Glaucoma (OAG) orOcular Hypertension (OH) in an eye by reducing intraocular pressure(IOP) in the eye, wherein the latanoprost is administered from alacrimal implant comprising a sustained release formulation of the 95 μgof latanoprost and the latanoprost is released in a therapeuticallyeffective dose from the lacrimal implant over a treatment period of atleast 8 weeks, wherein the IOP is reduced by at least 4 mm Hg from abaseline at week 8.

E23. A lacrimal implant comprising a unit dosage of about 95 μg oflatanoprost for use in the treatment of Open Angle Glaucoma (OAG) orOcular Hypertension (OH) in an eye by reducing intraocular pressure(IOP) in the eye, wherein the latanoprost is administered from alacrimal implant comprising a sustained release formulation of the 95 μgof latanoprost and the latanoprost is released in a therapeuticallyeffective dose from the lacrimal implant over a treatment period of atleast 12 weeks, wherein the IOP is reduced by at least 4 mm Hg from abaseline at week 12.

E24. A lacrimal implant drug delivery system comprising a unit dosage ofabout between 140 and 200 μg of latanoprost for use in the treatment ofOpen Angle Glaucoma (OAG) or Ocular Hypertension (OH) in an eye byreducing intraocular pressure (IOP) in the eye, comprising: providingthe unit dosage of about between 140 and 200 μg of latanoprost to an eyeover a treatment period of at least 4 weeks, wherein the latanoprost isadministered from a lacrimal implant comprising a sustained releaseformulation of the latanoprost and the latanoprost is released in atherapeutically effective dose from the lacrimal implant over thetreatment period, wherein the IOP is reduced by at least 5 mm Hg from abaseline at week 4.

E25. A lacrimal implant drug delivery system comprising a unit dosage ofabout between 140 and 200 μg of latanoprost for use in the treatment ofOpen Angle Glaucoma (OAG) or Ocular Hypertension (OH) in an eye byreducing intraocular pressure (IOP) in the eye, comprising: providingthe unit dosage of about between 140 and 200 μg of latanoprost to an eyeover a treatment period of at least 8 weeks, wherein the latanoprost isadministered from a lacrimal implant comprising a sustained releaseformulation of the latanoprost and the latanoprost is released in atherapeutically effective dose from the lacrimal implant over thetreatment period, wherein the IOP is reduced by at least 5 mm Hg from abaseline at week 8.

E26. A lacrimal implant drug delivery system comprising a unit dosage ofabout between 140 and 200 μg of latanoprost for use in the treatment ofOpen Angle Glaucoma (OAG) or Ocular Hypertension (OH) in an eye byreducing intraocular pressure (IOP) in the eye, comprising: providingthe unit dosage of about between 140 and 200 μg of latanoprost to an eyeover a treatment period of at least 12 weeks, wherein the latanoprost isadministered from a lacrimal implant comprising a sustained releaseformulation of the latanoprost and the latanoprost is released in atherapeutically effective dose from the lacrimal implant over thetreatment period, wherein the IOP is reduced by at least 5 mm Hg from abaseline at week 12.

E27. A lacrimal implant drug delivery system comprising a unit dosage ofabout 190 μg of latanoprost for use in the treatment of Open AngleGlaucoma (OAG) or Ocular Hypertension (OH) in an eye by reducingintraocular pressure (IOP) in the eye, comprising: providing the unitdosage of about 190 μg of latanoprost to an eye over a treatment periodof at least 4 weeks, wherein the latanoprost is administered from alacrimal implant comprising a sustained release formulation of thelatanoprost and the latanoprost is released in a therapeuticallyeffective dose from the lacrimal implant over the treatment period,wherein the IOP is reduced by at least 5 mm Hg from a baseline at week4.

E28. A lacrimal implant drug delivery system comprising a unit dosage ofabout 190 μg of latanoprost for use in the treatment of Open AngleGlaucoma (OAG) or Ocular Hypertension (OH) in an eye by reducingintraocular pressure (IOP) in the eye, comprising: providing the unitdosage of about 190 μg of latanoprost to an eye over a treatment periodof at least 8 weeks, wherein the latanoprost is administered from alacrimal implant comprising a sustained release formulation of thelatanoprost and the latanoprost is released in a therapeuticallyeffective dose from the lacrimal implant over the treatment period,wherein the IOP is reduced by at least 5 mm Hg from a baseline at week8.

E29. A lacrimal implant drug delivery system comprising a unit dosage ofabout 190 μg of latanoprost for use in the treatment of Open AngleGlaucoma (OAG) or Ocular Hypertension (OH) in an eye by reducingintraocular pressure (IOP) in the eye, comprising: providing the unitdosage of about 190 μg of latanoprost to an eye over a treatment periodof at least 12 weeks, wherein the latanoprost is administered from alacrimal implant comprising a sustained release formulation of thelatanoprost and the latanoprost is released in a therapeuticallyeffective dose from the lacrimal implant over the treatment period,wherein the IOP is reduced by at least 4 mm Hg from a baseline at week12.

E30. A lacrimal implant drug delivery system comprising a unit dosage ofabout 141 μg of latanoprost for use in the treatment of Open AngleGlaucoma (OAG) or Ocular Hypertension (OH) in an eye by reducingintraocular pressure (IOP) in the eye, comprising: providing the unitdosage of about 141 μg of latanoprost to an eye over a treatment periodof at least 8 weeks, wherein the latanoprost is administered from alacrimal implant comprising a sustained release formulation of thelatanoprost and the latanoprost is released in a therapeuticallyeffective dose from the lacrimal implant over the treatment period,wherein the IOP is reduced by at least 5 mm Hg from a baseline at week8.

E31. A lacrimal implant drug delivery system comprising a sustainedrelease formulation of a therapeutic agent for use in the treatment ofOpen Angle Glaucoma (OAG) or Ocular Hypertension (OH) in an eye,comprising: (a) providing a first lacrimal implant comprising thesustained release formulation of a therapeutic agent for treating OAG orOH; (b) providing a second lacrimal implant that does not comprise thetherapeutic agent; and (c) inserting the first and second lacrimalimplant through an upper and lower punctum into a lacrimal canaliculusof the same eye wherein the therapeutic agent is released in atherapeutically effective dose from the first lacrimal implant on asustained basis over at least four (4) weeks.

E32. A lacrimal implant drug delivery system comprising a sustainedrelease formulation of a therapeutic agent for use in the treatment ofOpen Angle Glaucoma (OAG) or Ocular Hypertension (OH) in an eye,comprising: (a) providing a first lacrimal implant comprising thesustained release formulation of a therapeutic agent for treating OAG orOH; (b) providing a second lacrimal implant that does not comprise thetherapeutic agent; and (c) inserting the first and second lacrimalimplant through an upper and lower punctum into a lacrimal canaliculusof the same eye wherein the therapeutic agent is released in atherapeutically effective dose from the first lacrimal implant on asustained basis over at least eight (8) weeks.

E33. A lacrimal implant drug delivery system comprising a sustainedrelease formulation of a therapeutic agent for use in the treatment ofOpen Angle Glaucoma (OAG) or Ocular Hypertension (OH) in an eye,comprising: (a) providing a first lacrimal implant comprising thesustained release formulation of a therapeutic agent for treating OAG orOH; (b) providing a second lacrimal implant that does not comprise thetherapeutic agent; (c) inserting the first and second lacrimal implantthrough an upper and lower punctum into a lacrimal canaliculus of thesame eye; and (d) releasing the therapeutic agent from the firstlacrimal implant as a therapeutically effective dose on a sustainedbasis over at least twelve (12) weeks.

E34. A lacrimal implant drug delivery system comprising a sustainedrelease formulation of a therapeutic agent for use in the treatment ofOpen Angle Glaucoma (OAG) or Ocular Hypertension (OH) in an eye byreducing intraocular pressure (IOP) in the eye, comprising: (a)measuring the IOP of the patient to obtain a baseline IOP beforetreatment; (b) providing the therapeutic agent for treating OAG or OH asa sustained release formulation; (c) delivering the sustained releaseformulation to the eye using the lacrimal implant comprising thesustained release formulation; and (d) releasing the therapeutic agentto the eye on a sustained basis over at least 8 weeks wherein the IOP isreduced by at least 4 mmHg from baseline at week 8.

E35. A lacrimal implant drug delivery system comprising a sustainedrelease formulation of a therapeutic agent for use in the treatment ofOpen Angle Glaucoma (OAG) or Ocular Hypertension (OH) in an eye byreducing intraocular pressure (IOP) in the eye, comprising: (a)measuring the IOP of the patient to obtain a baseline IOP beforetreatment; (b) providing the therapeutic agent for treating OAG or OH asa sustained release formulation; (c) delivering the sustained releaseformulation to the eye using a lacrimal implant comprising the sustainedrelease formulation; and (d) releasing the therapeutic agent to the eyeon a sustained basis over at least 12 weeks wherein the IOP is reducedby at least 4.0 mmHg from baseline at week 12.

E36. A lacrimal implant drug delivery system comprising a sustainedrelease formulation of a therapeutic agent for use in the treatment ofOpen Angle Glaucoma (OAG) or Ocular Hypertension (OH) in an eye byreducing intraocular pressure (IOP) in the eye, comprising: (a)measuring the IOP of the patient to obtain a baseline IOP beforetreatment; (b) providing the therapeutic agent for treating OAG or OH asa sustained release formulation; (c) delivering the sustained releaseformulation to the eye using a lacrimal implant comprising the sustainedrelease formulation; and (d) releasing the therapeutic agent to the eyeon a sustained basis over at least 12 weeks wherein the IOP is reducedby at least 5.0 mmHg from baseline at week 12.

The following Examples are provided to illustrate exemplary embodimentsof the invention and are not to be construed as limiting the scope ofthe present invention.

EXAMPLES Example 1—Evaluation of Safety and Efficacy of the LatanoprostPunctal Plug Delivery System (L-PPDS) Containing Latanoprost

A Phase II, open-label, clinical study was conducted in human subjectswith ocular hypertension (OH) or open-angle glaucoma (OAG) to evaluatesafety and efficacy of the latanoprost punctal plug delivery system(L-PPDS).

The Phase II trial featured simultaneous placement of punctal plugs inboth the upper and lower puncta for delivery of a daily drug load with agoal of enabling comparable clinical outcomes to that of dailyadministered Xalatan® eye drops. The overall objective was a meanreduction in IOP of 5 mm Hg or greater. The primary endpoint in thisPhase II study was a mean change in IOP from baseline (measured as mmHg) at 2 weeks. Secondary endpoints were the mean change in IOP frombaseline at 4 weeks and mean percentage change in IOP at 2 weeks and 4weeks. A total of 95 ITT (Intent to Treat) subjects were included in theL-PPDS treatments in this study. The mean IOP as baseline was 25.8 mm HGfor this group (with a range of baseline of 22.5 mm Hg to 33 mm Hg).

After 2 weeks of L-PPDS treatment, IOP showed a statisticallysignificant mean change from baseline of −6.2 mm Hg (95% C.I. −6.8,−5.6). At the end of week 2, 73% of subjects showed an IOP reduction vs.baseline of 5 mm Hg or greater and 51% of subjects showed a reduction of6 mm Hg or greater. The mean percentage change in IOP from baseline at 2weeks was −24.3%, which was statistically significant (95% C.I. −26.7,−21.9).

After 4 weeks of L-PPDS treatment, IOP showed a statisticallysignificant mean change from baseline of −5.7 mm Hg (95% C.I. −6.5,−4.9). At the end of 4 weeks, 60% of subjects showed an IOP reductionvs. baseline of 5 mm Hg or greater and 47% of subjects showed areduction of 6 mm or greater. The mean percentage change in IOP frombaseline at 4 weeks was also statistically significant at 22.3% (95%C.I. −25.4, −19.2).

Subjects were fitted with L-PPDS containing specified latanoprostconcentrations in the upper L-PPDS (46 μg) and the lower L-PPDS (95 μg).

Study Procedures

During the screening visit, the subjects were fitted with the trialpunctal plugs for approximately 15 minutes to 2 hours to assess fittingand eligibility. Pre-washout IOP measurements were determined in eacheye of the patient, and adverse device events (ADEs) were alsomonitored. After the trial fitting, subjects began the washout period inwhich subjects were discontinued from topical prostaglandin therapy toassess IOP eligibility for a minimum of 4 weeks and to a maximum of 6weeks.

After the washout, baseline IOP was measured in each eye of a patient ontwo separate visits that were 2 to 4 days apart (Day −2 and Day 0 studyvisits), after the patient had washed out of previous topicalprostaglandin therapy.

At the start of the study (Day 0), each patient had an L-PPDS insertedbilaterally into each puncta of each eyes and inspected thereafter ateach visit. If an L-PPDS was spontaneously extruded, one replacementL-PPDS per patient was allowed. The L-PPDS were removed at the Week 4visit.

After placement of the L-PPDS, subjects were monitored for anytreatment-emergent or adverse events (Aes) during the 4-week treatmentperiod. Subjects had weekly follow-up visits with the last study visitat Week 4. Tear volume was measured by a Schirmer test with anesthesiaover 5 minutes at Day 0 and at the last visit. Visual acuity wasmeasured with best correction using a Snellen chart at every visit.Biomicroscopy examinations were performed in each eye at every visit,including an inspection of the L-PPDS placement. Treatment-emergentocular and systemic Aes and concomitant medications were monitored atevery visit with standardized questioning techniques. Automatedperimetry was performed to measure visual fields at the last visit. Afunduscopy examination was performed at the last visit.

Goldmann IOP measurements (the average of 3 measurements) were measuredin each eye at every visit. The baseline IOP was taken on two separatedays, at least 48 hours apart. Specifically, IOP measurements were takenat 8:30 am (±30 minutes) at each visit.

L-PPDS

Each L-PPDS for the upper puncta was of a proprietary punctal plugdesign and had a latanoprost strength of 46 μg. Inactive components weremedical grade silicone, polyimide tubing, DMPC, cyanoacrylate medicalgrade adhesive, and 2% green colorant. Each L-PPDS was supplied in aseparate sterilized mylar foil pouch.

Each L-PPDS for the lower puncta was of a proprietary punctal plugdesign and had a latanoprost strength of 95 μg. Inactive components aremedical grade silicone, polyimide tubing, DMPC, cyanoacrylate medicalgrade adhesive, and 2% green colorant. L-PPDS for the lower puncta werepreloaded on an insertion tool. Each L-PPDS and insertion tool weresupplied in a tray contained in a sterilized mylar foil pouch.

FIG. 13 shows the mean reduction in intraocular pressure (IOP) frombaseline in weeks during the treatment period. FIG. 14 shows the percentof subjects that recorded an IOP reduction of ≥5 mm Hg from baseline, ≥6mm Hg from baseline, and ≥7 mm Hg from baseline, in weeks.

A secondary endpoint in the study was the percentage change in averageIOP from baseline at 2 weeks and 4 weeks for L-PPDS treatment. FIG. 15shows the mean reduction in IOP from baseline in weeks during thetreatment period. At 2 weeks, the percentage change from baseline of−24.3% (95% C.I. −26.7, −21.9) was statistically significant, and at 4weeks, the percentage change from baseline of −22.3% (95% C.I. −25.4,−19.2) was also statistically significant.

The IOP reduction results are summarized in the Table 4:

TABLE 4 Mean change and % change in IOP in weeks for L-PPDS containinglatanoprost concentration of 141 μg Mean Change in IOP from % Change inIOP Baseline (95% C.I.) from Baseline (95% C.I.) 2 weeks −6.2 (−6.8,−5.6) −24.3% (−26.7%, −21.9%) (n = 70) 4 weeks −5.7 (−6.5, −4.9) −22.3%(−25.4%, −19.2%) (n = 53)

Plug Retention Results

The lower punctal plug achieved 94% or greater retention per subjectacross the duration of the 4 week study. The upper punctal plug showed aretention rate of 40% per subject across the duration of the study.

Assessment of Treatment Safety and Tolerability

The L-PPDS was well tolerated over the testing period. The majority ofAEs were ocular in nature, however, none were serious AEs. The mostfrequently reported AE was mild to moderate tearing. Few subjectsexperienced any discomfort related to the punctal plugs with mostsubjects having either no awareness or mild awareness of the punctalplugs by week 4.

Example 2—Comparison of Clinical Studies of the L-PPDS at DifferentDosages

A number of clinical studies have been conducted to assess the safety,efficacy, and dosing for L-PPDS treatment in more than 300 humansubjects with OH or OAG. These studies have investigated the preliminarysafety and efficacy of L-PPDS over the dose range of 3.5 to 95 μg pereye, primarily delivered via an L-PPDS positioned in the lower puncta.See, for example, ClinicalTrials.gov Identifier: NCT00967811, “AnOpen-Label, Phase 2 Study of Different Formulations (E1 and E2) of theLatanoprost Punctal Plug Delivery System (L-PPDS) in Subjects WithOcular Hypertension (OH) or Open-Angle Glaucoma (OAG),” Study StartDate: August 2009, (other study ID number: PPL GLAU 07), incorporatedherein by reference; and ClinicalTrials.gov Identifier: NCT01037036, “AnOpen-Label, Phase 2 Study of the Latanoprost Punctal Plug DeliverySystem (L-PPDS) With Adjunctive Xalatan® Eye Drops in Subjects WithOcular Hypertension (OH) or Open-Angle Glaucoma (OAG),” Study StartDate: Dec. 17, 2009, (other study ID number: PPL GLAU 08), incorporatedherein by reference. Based on the published clinical results for IOPreduction associated with Xalatan® eye drops, the magnitude of mean IOPreductions has been less than expected; however, results for L-PPDS showthat some subjects had IOP reductions that would be expected withXalatan®. All studies have occluded only one punctum per eye. Theoverall mean IOP reduction for the L-PPDS was similar among most of thestudies (range −3 to −5 mmHg), regardless of latanoprost concentrationfrom 3.5 μg to 95 μg per eye. Specifically, the mean IOP reductionaccording to the clinical study described in Example 1 and the clinicalstudies of the L-PPDS containing latanoprost concentrations of 44 μg and81 μg, see ClinicalTrials.gov Identifier: NCT00820300, “An Open-Label,Phase 2 Study of the Latanoprost Punctal Plug Delivery System (L-PPDS)in Subjects With Ocular Hypertension (OH) or Open Angle Glaucoma (OAG),”Study Start Date: January 2009, (other study ID number: PPL GLAU 03),incorporated herein by reference, and two different 95 μg formulationswere compared, where the two 95 μg formulations (E1 and E2) weredeveloped to deliver different average daily doses, seeClinicalTrials.gov Identifier: NCT00967811, “An Open-Label, Phase 2Study of Different Formulations (E1 and E2) of the Latanoprost PunctalPlug Delivery System (L-PPDS) in Subjects With Ocular Hypertension (OH)or Open-Angle Glaucoma (OAG),” Study Start Date: August 2009, (otherstudy ID number: PPL GLAU 07), incorporated herein by reference. Table 5summarizes the range of mean IOP change from baseline during the first 4weeks period of the L-PPDS treatments in the clinical studies. Table 6summarizes the IOP change (mm Hg) in number (percent) of subjects inweeks 2 and 4.

TABLE 5 Mean IOP change from baseline in clinical studies Study ID GLAU11 GLAU 03 GLAU 07 (Example 1) L-PPDS 44 μg 81 μg 95 μg E1 95 μg E2 141μg Formulation (N = 57) (N = 53) (N = 42) (N = 41) (N = 95) Range ofMean −3.5 to −3.6 −3.0 to −3.4 −3.5 to −4.2 −3.9 to −4.7 −5.7 to −6.8IOP Change from Baseline: Weeks 1 to 4 (mmHg)

TABLE 6 IOP Changes in % Subjects Study ID GLAU 03 GLAU 07 GLAU 11L-PPDS 44 μg 81 μg 95 μg E1 95 μg E2 141 μg Formulation (N = 57) (N =53) (N = 42) (N = 41) (N = 95) Week 2 ≥5 31% 25% 31% 22% 73% ≥6 24% 16%17% 17% 51% ≥7 16% 4% 12% 15% 36% Week 4 ≥5 35% 29% 38% 31% 60% ≥6 23%22% 15% 21% 47% ≥7 8% 12% 13% 10% 28%

No mean IOP change of ≥5 mm Hg was observed within the 4 weeks durationof treatments of L-PPDS containing latanoprost concentrations of 44 μg,81 μg, and 95 μg. The mean IOP reductions were significantly greaterwith L-PPDS containing a combined latanoprost concentration of 141 μgrecorded in the clinical study described in Example 1, compared withL-PPDS containing lower lantanoprost doses. The mean IOP change frombaseline for L-PPDS with a combined latanoprost concentration of 141 μgwas substantial, from −5.7 mm Hg to −6.8 mm Hg.

Example 3—Method of Preparation L-PPDS (95 μg) Cores

NuSil Silicone MED6385 part A was stirred for a minimum of 5 minutes,and 63 mg of which was weighed and transferred onto a glass slide. Tothe same glass slide was added Latanoprost (obtained from EverlightChemical, Taipei, Taiwan) (48 mg), dimyristoylphosphatidylcholine (DMPC)(9 mg) and NuSil Med6382 crosslinker (2.4 mL). Using a 0.5 μL HamiltonSyringe, Nusil MED6385 part B (0.348 μL) was transferred directly onto amini spatula. The latanoprost, NuSil MED6382 crosslinker, NuSil SiliconeMED-6385 part B and DMPC were mixed together for 2-5 minutes to form ahomogenous mixture. The resulting mixture was combined with NuSilSilicone MED6385 part A and was mixed for another 2 minutes to form ahomogenous mixture, which was immediately transferred into a previouslyprepared syringe assembly. The syringe was then attached to polyimidetubing (0.024″ OD) by way of an adapter. The polyimide tubing was keptat a temperature of 4° C. by way of a cooling jacket. After 2 minutes,the mixture was injected into the polyimide tubing by increasing thepressure of the system to 40 psi over 2.5 minutes. Once the mixture hadextruded through the polyimide tubing to the end, the tubing was cut andboth ends were clamped. The tube was placed into a humidity chamber at40° C. and 80% relative humidity for 24-96 hours to cure the silicone,and the tubing was cut into 1.0 mm lengths. Loctite 4305 (HenkelAdhesives Technologies, Ltd.) was applied to the bottom end of the cuttubing and cured for 20 seconds in a 100 W UV curing chamber. Thesecores were then inserted into the cavity of punctal plugs with the gluedend positioned in the bottom of the cavity.

Example 4—PP DEV 05: A Device Evaluation Study to Further Assess thePhysical and Clinical Characteristics of Prototype Punctal Plug DesignIterations Study Objective

To evaluate the physical and clinical performance characteristics ofpunctal plug design iterations.

Study Design

This is a multicenter, device assessment, feasibility study to assessthe physical and clinical performance characteristics of prototypepunctal plugs. Up to approximately 500 subjects will be enrolled at 5-15sites in the US. No drug treatment will be administered. The study willevaluate the physical (handling) and clinical (comfort, tearing,retention) characteristics of punctal plug prototypes. The study will beiterative, with data monitored on an ongoing basis and designmodifications to the punctal plugs made if further improvements areindicated. An investigational plug detection aid may also be evaluated.

Subjects will be enrolled into 1 of 2 groups. Group 1 will undergo two12-week plug placement periods. Group 2 will undergo two 2-week plugplacement periods followed by one 12-week plug placement period. Plugplacement will be attempted in the lower and upper puncta of both eyes.Placement must be successful in both the upper and lower puncta of atleast 1 eye for the subject to be eligible for the study. The Sponsorwill inform the sites in advance in writing which plug iterations to usefor each subject for each placement period. For Group 1, study visitswill occur at Day 0, and Weeks 4, 8, 12, 16, 20 and 24, with plugplacement at the Day 0 and Week 12 visits. For Group 2, study visitswill occur at Day 0 and Weeks 1, 2, 3, 4, 8, 12 and 16, with plugplacement at Day 0, Week 2, and Week 4.

A subject who completes or is withdrawn from the Group 1 or Group 2treatment schedule may be re-enrolled into the study (to either Group 1or Group 2). A re-enrolled subject will be assigned a new subject numberand undergo screening procedures again.

Safety will be assessed throughout the study.

Study Population

Subjects will be male and female volunteers, age 50 years or older. Mainexclusion criteria will include:

-   -   History of, or active, lid disease requiring lid scrubs (e.g.,        moderate or severe blepharitis, dacryocystitis, meibomianitis)    -   Structural lid abnormalities (e.g., ectropion, entropion)    -   Active anterior segment inflammatory disease    -   Ocular allergies    -   Habitual eye rubbing    -   Previous intolerance of punctal plugs (e.g., inflammatory        reaction, granuloma, dacryocystitis, etc. due to punctal plug        wear)    -   Laser eye surgery within the last 3 months or incisional eye        surgery within the last 6 months.

Study Devices

The punctal plugs will be placed bilaterally into the upper and lowerpuncta using an investigational insertion tool provided with the plug orophthalmic forceps. The techniques for insertion and removal are similarto the procedures for other commercial punctal plugs.

Study Variables

Device Performance:

-   -   Retention rates    -   Insertion success    -   Ease of use

Tolerability

-   -   Comfort    -   Tearing

Safety

-   -   Adverse device events (ADEs)    -   Biomicroscopy

Study Procedures and Assessments:

Device Performance:

-   -   For subjects who provide additional consent, photographs of the        punctal plugs may be taken after their placement to observe        their location in the lid margin; videography of punctal plug        placement and removal procedures may be performed for future        physician training. In-person observational physician training        of punctal plug placement and removal procedures may also occur.

Tolerability:

-   -   Subjects will rate the acceptability of tearing and comfort        according to a visual analog scale at every visit.

Safety:

-   -   Biomicroscopy will be performed in each eye and ADEs will be        collected at every study visit.

Sample Size and Statistical Analyses:

-   -   The sample size is based on clinical judgment and is believed to        be sufficient to meet the study objectives. All study variables        will be summarized descriptively. ADEs will be coded using the        Medical Dictionary for Regulatory Activities (MedDRA) and        summarized descriptively by system organ class and preferred        term.

Example 5: GLAU 12: A Phase 2 Dose Evaluation Study for the LatanoprostPunctal Plug Delivery System (L-PPDS) in Subjects With OcularHypertension (OH) or Open-Angle Glaucoma (OAG)

The Phase II trial featured simultaneous placement of punctal plugs inboth the upper and lower puncta for delivery of a daily drug load with agoal of enabling comparable clinical outcomes to that of dailyadministered Xalatan® eyedrops. The objective of this study was toevaluate the efficacy, safety and duration of effect of the L-PPDS attwo dose levels (141 μg and 190 μg).

Study PPL GLAU 11 (Example 1 and FIGS. 13-15) showed that occlusion ofboth puncta with the L-PPDS at a total latanoprost dose per eye of 141μg significantly reduced IOP for up to 4 weeks. This study, in which theleft eye has the same dose as PPL GLAU 11 and the right eye has a 95 μgL-PPDS in both the upper and lower puncta, is designed to replicate theresults of PPL GLAU 11 and to assess the effect of a higher dose. Inaddition, this study will run for 12 weeks to determine whether theeffect observed in PPL GLAU 11 is durable for a longer time period.

The latanoprost dose for the left eye (46 μg L-PPDS in the upper punctumand 95 μg L-PPDS in the lower punctum) was chosen in order to replicatethe dose used in Study PPL GLAU 11. The latanoprost dose for the righteye (95 μg L-PPDS in both the upper and lower puncta) was chosen becauseit is the highest dose currently attainable.

The highest latanoprost dose in this study (190 μg delivered over 3months) is equivalent to the amount in approximately 127 drops ofXalatan. The prescribed Xalatan dose over 3 months is 90 drops (1drop/day), so 190 μg latanoprost delivered over 3 months represents adose about one-third higher than that for Xalatan drops.

Main Study Design

Subjects diagnosed with bilateral OH or OAG who are treatment naïve ormanaged with up to 2 glaucoma medications were eligible for studyscreening. IOP eligibility was established at baseline prior toenrollment in the study.

After eligibility was established, subjects received treatment for 12weeks as follows:

-   -   Right eye: 95 μg L-PPDS inserted in the lower puncta and 95 μg        L-PPDS in the upper puncta.    -   Left eye: 95 μg L-PPDS inserted in the lower puncta and a 46 μg        L-PPDS in the upper puncta.

Addendum Study Design

The addendum study included subjects enrolled in the main study who hada decrease in IOP of >5 mmHg from baseline at Day 7 in response to two95 μg L-PPDS and who retained both plugs in at least 1 eye for at least4 weeks in the first treatment cycle. Eligible subjects started L-PPDSCycle 2 (C2) within 30 days of removal of L-PPDS in the main study. OnC2 Day 0, subjects had 95 μg L-PPDS inserted in the upper and lowerpuncta of both eyes for 8 weeks (C2). At the end of C2, another set of95 μg L-PPDS were inserted in the upper and lower puncta of both eyesfor 4 weeks (Cycle 3 [C3]). Subjects were followed up for assessment ofsafety and IOP effect with visits at 1, 2, 4, 6 and 8 weeks of C2, and1, 2 and 4 weeks of C3. Safety was monitored as in the main study.Analysis of IOP effect was primarily based on change from baseline inIOP measurements (the baseline value from the main study was used todetermine IOP change from baseline in subsequent cycles) andbetween-cycle comparisons.

Treatment

Main Study

Investigational L-PPDS for the lower puncta of both eyes was the L67design with a latanoprost dose of 95 μg. See, FIG. 33. InvestigationalL-PPDS for the upper puncta was the L69 design with a latanoprost doseof 95 μg for the right eye, and the L72 design with a latanoprost doseof 46 μg for the left eye.

The total latanoprost dose was 190 μg for the right eye and 141 μg forthe left eye.

At the Day 0 visit, subjects had the plugs inserted bilaterally into theupper and lower puncta. If any plug spontaneously extruded, it was to bereplaced with an L67 95-μg L-PPDS, if possible. The number ofreplacements was limited to 2, and once a subject lost plugs from botheyes, the subject was withdrawn from the study. The LPPDS was removed atthe Week 12 visit.

Addendum Study

Investigational L-PPDS for all puncta had a latanoprost dose of 95 μg.The total latanoprost dose was 190 μg/eye. Subjects underwent an 8-weekL-PPDS treatment cycle (C2) followed by a 4-week L-PPDS treatment cycle(C3). If any plug spontaneously extruded, it was to be replaced;however, once a subject lost a plug from each eye in C2, the remainingL-PPDS were removed, and the subject started C3. Once a subject lost aplug from each eye in C3 the subject was withdrawn from the study.

Subjects were followed up for assessment of safety and IOP effect.Safety was monitored with adverse events (AEs), IOP, Snellenbest-corrected visual acuity (BCVA) or pinhole visual acuity (methodshould be consistent for a given subject throughout the study),biomicroscopy, subject tearing and comfort assessments, automatedperimetry, and funduscopy. Analysis of IOP effect was primarily based onchange from baseline in IOP measurements.

To address the study objective of evaluating the safety and IOP loweringeffects of the L-PPDS, IOP results were compared to baseline IOP. TheIOP entry criteria included precautions to ensure that washout (ifapplicable) is complete and baseline IOP is stable (e.g., minimum 5 mmHgchange from pre-screening and less than 3 mmHg difference in IOP between2 baseline visits 2 days apart).

Providing different treatments to each of a subject's eyes necessitatedthat the eyes be independent of each other for the results to be valid.

Number of Subjects and Statistical Analyses

Approximately 55 subjects were enrolled to have 35 eyes available foreach treatment for the evaluable analysis. With a sample size of 35evaluable eyes in each treatment group, a 2-sided 95.0% confidenceinterval (CI) for the mean IOP change from baseline extended 1.0 mm Hgfrom the observed mean, assuming that the standard deviation was knownto be 3.0 mm Hg and the CI is based on the large sample z statistic. Thestandard deviation of 3.0 mm Hg used in the above sample sizecalculation was based on results of the L-PPDS clinical studiesconducted to date.

The primary efficacy variable was the change from baseline in IOPmeasurements and the primary analysis time point will be at 4 weeks.Other IOP variables listed above were secondary efficacy variables. Foranalyses using the intent-to-treat (ITT) data set, all data from allsubjects with at least 1 follow-up IOP measurement were included. Foranalyses using the evaluable (EVAL) data set, data from subjects orvisits with significant protocol deviations were excluded.

Inclusion Criteria

To be eligible for the study, subjects must fulfill all of the followingcriteria:

Subjects who are men or women >18 years old.

Subjects diagnosed with bilateral OAG or OH. Subjects may be treatmentnaïve or managed with up to 2 medications (combination products such asCosopt® will be considered 2 medications).

-   -   For subjects on a topical prostaglandin treatment (as        monotherapy or in combination): Screening IOP is ≤21.0 mmHg.    -   Subjects who can be fitted with L-PPDS in all 4 puncta at Day 0.    -   Subjects whose baseline IOP measured at 2 baseline visits (i.e.,        average of IOP values obtained at 2 baseline visits) meets the        following criteria in each eye after the screening period:        -   a. ≥22.0 mmHg        -   b. ≤34.0 mmHg    -   For subjects on topical prostaglandin therapy at screening: Is        increased ≥5.0 mmHg from screening.    -   Subjects whose baseline IOP measurements in each eye are ≤3 mmHg        apart between 2 sequential baseline visits.    -   Subjects who have central corneal thickness in each eye ≥500 μm        and ≥600 μm.    -   Subjects who have Snellen BCVA 20/100 or better in each eye.    -   Subjects who are women of child-bearing potential must not be        pregnant or lactating, must have a negative pregnancy test at        screening and must be practicing an adequate method of birth        control. Acceptable methods of birth control include        intrauterine device (IUD); oral, dermal (“patch”), implanted or        injected contraceptives; tubal ligation; and barrier methods        with spermicide.    -   Subjects who sign an approved informed consent form for the        study.    -   Subjects who are willing to comply with the protocol.

Study Procedures and Assessments

IOP measurements were determined in each eye at the screening visit. Theduration of the screening period depended on the time required forwashout of topical ocular hypotensive therapy. Washout was not requiredfor treatment-naïve subjects.

After the screening period, IOP measurements were determined in each eyeon 2 separate visits, 2 to 4 days apart. For treatment-naïve subjectsthe initial screening visit was considered as the first visit fordetermination of baseline IOP.

The L-PPDS treatment period was 12 weeks. Study visits occurred at Days1, 3, 7, and 14, and Weeks 3, 4, 6, 8, 10 and 12. (Subjects who wereprostaglandin-naïve at study entry had a visit at Week 14 after theXalatan run-out period is complete.) There was a follow-up telephonecall 3 days after the last visit. The following tests and procedureswere performed during study follow-up.

-   -   Goldmann IOP measurements (the average of 3 measurements) will        be measured in each eye at every visit. The baseline IOP will be        taken on 2 separate days, at least 48 hours apart. IOP        measurements must be taken at 8:30 am (±30 minutes) at each        visit.    -   Visual acuity will be measured with best correction or pinhole        using a Snellen chart at every visit; the method (best        correction or pinhole) should be consistent for a given subject        throughout the study.    -   Biomicroscopy examinations, including an inspection of L-PPDS        placement, will be performed in each eye at every visit.    -   Subjects will rate the acceptability of the tearing and comfort        level of the plugs, and the frequency of tearing, on a visual        analog scale at each visit starting at Day 0. Subjects will also        be asked at the end of the study which they prefer: punctal        plugs or eye drops.    -   Treatment-emergent ocular and systemic AEs and concomitant        medications will be monitored at every visit with standardized        questioning techniques.    -   Investigators will rate the ease of insertion of the plugs.    -   Automated perimetry will be performed to measure visual fields        at screening and Week 12.    -   A funduscopy examination will be performed at screening and Week        12.

All ocular procedures were performed by an experienced and appropriatelyqualified individual(s). Subjects who discontinue the study treatmentprematurely underwent the tests and procedures for the last visit.

It is unexpected for the L-PPDS to malfunction and release all or amajor portion of its contents in a short period of time. The expectedexposure to latanoprost (190 μg delivered over 3 months) is within thesafety profile established in a series of ocular toxicity studiesconducted to support the FDA approval of Xalatan. Specifically, noadverse effects were observed in rabbits with twice-daily ocularinstillation of latanoprost doses up to 50 μg per eye for 52 weeks (100μg/eye/day). In a similar 52-week ocular study in cynomolgus monkeys,the only effects observed at doses up to 50 μg/eye given twice daily(100 μg/eye/day) were a reversible change in the aspect of the palpebralfissure and a non-reversible increase in iris pigmentation, which werenot judged to be deleterious (Xalatan Product Monograph 2011). In astudy of 28 healthy volunteers, in which 1 drop of latanoprost 50 μg/mLwas administered once daily in 1 eye and 4 times daily in the other eyefor 2 weeks, transient photophobia, cells, and mild flare were commonduring the 4-dose regimen, but these effects resolved spontaneouslywithout cessation of treatment (Linden and Alm 2001).

Results: Interim analysis (n=83) showed sustained mean IOP decreasesfrom baseline at Week 8 greater than 5 mmHg for the 190 μg dose, withsomewhat lower levels for the 141 μg dose.

Final Study Results: A total of 57 subjects enrolled in the study. Menand women were represented approximately evenly (51% and 49%,respectively). Subjects were Caucasian (37%), Hispanic (32%), Black(26%), and Asian (5%), with an average age of 65 years. Most eyes wereassessed to have primary open angle glaucoma (74% right eyes, 69% lefteyes), while the other eyes had ocular hypertension (26% right eyes, 31%left eyes). Mean IOP at screening was 18.79 mmHg for right eyes and18.97 mmHg for left eyes; by baseline (after the washout period) meanIOP had increased to 24.75 mmHg for right eyes and 24.66 mmHg for lefteyes.

At Week 4, 47 subjects (82%) had IOP measured; at Week 12, 35 subjects(61%) had IOP measured. A total of 44 subjects (77%) completed the mainstudy (Week 12). Twelve subjects (21%) participated in the Xalatanrun-out. Nineteen subjects (100%) entered the addendum study, and 12(62%) completed C2 (Week 8) and had IOP measured at that visit. Sixsubjects (100%) began C3, and 5 subjects (83%) completed C3 (Week 4) hadIOP measured at that visit.

The ITT data set included 109 eyes, EVAL included 101 eyes, and safetyincluded all 57 subjects. Five subjects received 190 μg latanoprost inboth eyes (95 μg L-PPDS in upper and lower puncta of both eyes) becausethe 46 μg L-PPDS was not available when they started treatment.Consequently, although the ITT data set included 57 subjects (114 eyes),the average IOP from the eyes of the 5 subjects who received 190 μglatanoprost in both eyes was used for the analysis, so ITT results arebased on 109 data points (eyes).

Treatment with L-PPDS resulted in significant mean IOP decreases frombaseline across all time points (Table 7 and FIG. 23) in the main study.

TABLE 7 Summary of IOP (mmHg) Results ITT (N = 109 eyes) EVAL (N = 101eyes) Visit (Main Study) Observed IOP Excl^(b) Observed IOP Excl^(b) Day14 n 99   83   91   76   Mean IOP 18.9 18.8 19.0 18.8 Mean IOP ↓ −5.8−6.0 −5.8 −5.9 CI (−6.40, −5.26) (−6.58, −5.42) (−6.37, −5.23) (−6.51,−5.36) Week 4 n 89   73   81   67   Mean IOP 19.3 19.3 19.2 19.2 MeanIOP ↓ −5.6 −5.6 −5.7 −5.7 CI (−6.12, −5.05) (−6.13, −5.09) (−6.27,−5.16) (−6.21, −5.16) Week 8 n 70   54   62   48   Mean IOP 20.6 20.320.5 20.2 Mean IOP ↓ −4.3 −4.7 −4.3 −4.7 CI (−4.96, −3.64) (−5.29,−4.00) (−5.06, −3.59) (−5.37, −3.95) Week 12 n 67   48   61   44   MeanIOP 20.8 21.1 20.8 21.2 Mean IOP ↓ −4.0 −3.9 −4.1 −3.8 CI (−4.77, −3.28)(−4.77, −3.01) (−4.86, −3.28) (−4.75, −2.89)

Significant reduction in mean IOP was observed at Weeks 4 and 6 (−5.4and −5.8 mmHg, respectively, in the ITT group. No meaningful differencein IOP results was observed between eyes (ie, 190 μg and 141 μglatanoprost).

In the main study, retention rate of L-PPDS in the lower puncta was ≥96%through Week 12. Retention of upper L-PPDS was 69%, 53%, and 48% atWeeks 4, 8, and 12, respectively. In C2, upper L-PPDS retention wasnotably higher than in the main study (90% and 88% at Weeks 4 and 8,respectively).

Study Conclusions: Treatment with L-PPDS in both puncta (totallatanoprost dose of either 190 or 141 μg/eye) resulted in a clinicallymeaningful and statistically significant reduction in IOP from baselineof approximately 6 mmHg after 4 weeks (primary endpoint).

Example 6: GLAU 13: A Randomized Phase 2 Study of the Effect of PlugPlacement on Efficacy and Safety of the Latanoprost Punctal PlugDelivery System (L-PPDS) in Subjects With Ocular Hypertension (OH) orOpen Angle Glaucoma (OAG)

Study PPL GLAU 11 (Example 1 and FIGS. 13-15) showed that occlusion ofboth puncta with the L-PPDS at a total latanoprost dose per eye of 141μg significantly reduced IOP for up to 4 weeks. This effect could havebeen due to the dose, double occlusion of the puncta, placement of theL-PPDS in the upper punctum, or a combination thereof. This study (GLAU13), in which the L-PPDS will be placed in either the upper or lowerpuncta, with the other punctum either left open or blocked by a punctalplug that does not contain latanoprost, will assess whether the effectobserved in Study PPL GLAU 11 was due to delivery of latanoprost fromthe upper punctum, or was a result of having both puncta blocked, thusincreasing the residence time of latanoprost in the tear film and makingmore drug available to the cornea. In addition, this study will run for12 weeks to determine the duration of effect.

Each eye in this study had one 95 μg L-PPDS. This dose was chosenbecause it is the highest dose available when only one lacrimal implantis utilized. The dose of 95 μg (delivered over 3 months) is equivalentto the amount in approximately 63 drops of Xalatan. The prescribedXalatan dose over 3 months is 90 drops (1 drop/day), so 95 μglatanoprost delivered over 3 months represents a dose about one-thirdlower than that for Xalatan drops.

Subjects diagnosed with bilateral OH or OAG who were treatment naïve ormanaged with up to 2 glaucoma medications were eligible for studyscreening. During the washout period subjects were discontinued fromglaucoma therapy (if applicable). Intraocular pressure (IOP) eligibilitywas established at baseline prior to enrollment in the study. Successfulplug insertion on Day 0 was required for study enrollment.

After eligibility was established, subjects received treatment for 12weeks. There were 3 different treatments studied, as follows:

Upper Punctum Lower Punctum Treatment A 95 μg L-PPDS Punctal plug (nolatanoprost) Treatment B 95 μg L-PPDS No plug Treatment C Punctal plug95 μg L-PPDS (no latanoprost)

The total dose of Latanoprost per eye was 95 μg.

Subjects received different treatments in each eye. Because there are 3different treatments, subjects were randomly assigned to 1 of 3 groupsto determine what treatment combination they would receive, as follows:

Eye Treatment Upper Punctum Lower Punctum Group 1 Right A 95 μg L-PPDSPunctal plug Left B 95 μg L-PPDS No plug Group 2 Right A 95 μg L-PPDSPunctal plug Left C Punctal plug 95 μg L-PPDS Group 3 Right B 95 μgL-PPDS No plug Left C Punctal plug 95 μg L-PPDS

Subjects were followed up for assessment of safety and IOP effect.Safety was monitored with adverse events (AEs), IOP, Snellenbest-corrected visual acuity (BCVA), biomicroscopy, subject tearing andcomfort assessments, automated perimetry, and funduscopy. Analysis ofIOP effect was primarily based on change from baseline in IOPmeasurements.

Discussion of Study Design

To address the study objective of evaluating the safety and IOP loweringeffects of the L-PPDS, IOP results were compared to baseline IOP. TheIOP entry criteria included precautions to ensure that washout (ifapplicable) was complete and baseline IOP was stable (e.g., minimum 5mmHg change from the start of screening and less than 3 mmHg differencein IOP between 2 baseline visits 2 days apart).

Providing different treatments to each of a subject's eyes necessitatesthat the eyes be independent of each other for the results to be valid.Studies have shown that the contralateral effect of prostaglandins isminimal, due to their rapid systemic metabolism, and using differenttreatments on each of a subject's eyes will produce valid andindependent results (Ziai et al., The effects on aqueous dynamics ofPhXA41, a new prostaglandin F2 α analogue, after topical application innormal and ocular hypertensive human eyes. Arch Ophthalmol.111:1351-1358 (1993); Realini et al., The uniocular drug trial andsecond-eye response to glaucoma medications. Ophthalmol. 111:421-426(2004)). Contralateral treatment is also a more efficient study designas it requires fewer subjects to be treated. The decision to usecontralateral treatment for this study was made in consultation withglaucoma experts.

Study Population

Approximately 80 subjects were enrolled in the study to have 35 eyesavailable for the evaluable analysis for each treatment. With a samplesize of 35 evaluable eyes for each treatment, a 2-sided 95.0% confidenceinterval (CI) for the mean IOP change from baseline will extend 1.0 mmHgfrom the observed mean, assuming that the standard deviation is known tobe 3.0 mmHg and the CI is based on the large sample z statistic. Thestandard deviation of 3.0 mmHg used in the above sample size calculationwas based on results of the L-PPDS clinical studies conducted to date.

Main Inclusion Criteria:

-   -   Diagnosed with bilateral OH or OAG and either treatment-naïve or        currently managed with up to 2 medications. Combination products        such as Cosopt® will be considered 2 medications.    -   For subjects on a topical prostaglandin treatment either as        monotherapy or in combination: Screening IOP is ≥21.0 mmHg.    -   Can be fitted with punctal plugs and L-PPDS on Day 0.    -   Baseline IOP measured at 2 baseline visits meets the following        criteria in each eye after the screening period:        -   c. ≥22.0 mmHg        -   d. ≤34.0 mmHg        -   e. For subjects on topical prostaglandin therapy at            screening: Is increased ≥5.0 mmHg from screening    -   Baseline IOP measurements are ≤3 mmHg apart between 2 sequential        baseline visits in each eye.    -   Central corneal thickness ≥500 μm and ≤600 μm in each eye.

Study Treatments L-PPDS Treatment

At the Day 0 visit, investigational L-PPDS with 95 μg of Latanoprost wasinserted into either the upper or lower puncta of each eye (depending onthe treatment group). The other punctum of each eye had either a solidpunctal plug (containing no latanoprost), or did not have a pluginserted, depending on the treatment group. The total latanoprost dosefor each eye was 95 μg. The plugs were removed at the Week 12 visit.

Study Variables

IOP, IOP change from baseline, and percentage IOP change from baseline;BCVA and change from baseline BCVA; Biomicroscopy examination variables;Subject tearing and comfort scores; Funduscopy variables; Automatedperimetry variables; Adverse events (AEs); Concomitant medications;Proportion of subjects who lose an L-PPDS/punctal plug; Proportion ofeyes that lose an L-PPDS/punctal plug; and Investigator assessment ofL-PPDS insertion

Study Procedures and Assessments

IOP measurements were determined in each eye at the screening visit. Theduration of the washout period depended on the time required for washoutof topical ocular hypotensive therapy. Washout was not required fortreatment-naïve subjects. After the washout period, IOP measurementswere determined in each eye on 2 separate visits, 2 to 4 days apart. Fortreatment-naïve subjects the initial screening visit was considered asthe first visit for determination of baseline IOP.

The L-PPDS treatment period was 12 weeks. Study visits occurred at Days1, 3, 7, and 14, and Weeks 3, 4, 6, 8, 10 and 12. (Subjects who wereprostaglandin-naïve at study entry will also have a visit at Week 14after the Xalatan run-out period is complete.) There was a follow-uptelephone call 3 days after the last visit. The following tests andprocedures were performed during study follow-up.

Goldmann IOP measurements (the average of 3 measurements) were measuredin each eye at every visit. The baseline IOP was taken on 2 separatedays, at least 48 hours apart. IOP measurements must be taken at 8:30 am(±30 minutes) at each visit.

Visual acuity was measured with best correction or pinhole using aSnellen chart at every visit; the method (best correction or pinhole)were consistent for a given subject throughout the study.

Biomicroscopy examinations, including an inspection of L-PPDS placementwas performed in each eye at every visit.

Subjects will rate the acceptability of the tearing and comfort level ofthe plugs, and the frequency of tearing, on a visual analog scale ateach visit starting at Day 0. Subjects were also asked at the end of thestudy which they prefer: punctal plugs or eye drops.

Treatment-emergent ocular and systemic AEs and concomitant medicationswere monitored at every visit with standardized questioning techniques.

Investigators rated the ease of insertion of the plugs.

Automated perimetry was performed to measure visual fields at screeningand Week 12.

A funduscopy examination was performed at screening and Week 12.

All ocular procedures are performed by an experienced and appropriatelyqualified individual(s). Subjects who discontinued the study treatmentprematurely underwent the tests and procedures for the last visit.

It is unexpected for the L-PPDS to malfunction and release all or amajor portion of its contents in a short period of time. The expectedexposure to latanoprost (95 μg delivered over 3 months) was within thesafety profile established in a series of ocular toxicity studiesconducted to support the FDA approval of Xalatan. Specifically, noadverse effects were observed in rabbits with twice-daily ocularinstillation of latanoprost doses up to 50 μg per eye for 52 weeks (100μg/eye/day). In a similar 52-week ocular study in cynomolgus monkeys,the only effects observed at doses up to 50 μg/eye given twice daily(100 μg/eye/day) were a reversible change in the aspect of the palpebralfissure and a non-reversible increase in iris pigmentation, which werenot judged to be deleterious (Xalatan Product Monograph 2011). In astudy of 28 healthy volunteers, in which 1 drop of latanoprost 50 μg/mLwas administered once daily in 1 eye and 4 times daily in the other eyefor 2 weeks, transient photophobia, cells, and mild flare were commonduring the 4-dose regimen, but these effects resolved spontaneouslywithout cessation of treatment (Linden and Alm, the effect onintraocular pressure of latanoprost once or four times daily. Br. J.Ophthalmol. 85:1163-1166 (2001)).

IOP Variables and Analyses

The primary efficacy variable was IOP change from baseline and theprimary analysis time point will be at Week 4. The secondary efficacyvariables were IOP and percentage IOP change from baseline.

Baseline IOP was defined as the average of 6 measurements: 3measurements taken on Day −2 (end of screening period) and 3measurements taken on Day 0 (before L-PPDS insertion).

The analyses of IOP variables were performed based on the values fromeach eye. For analyses using the ITT data set, all data from all eyeswith at least 1 follow-up IOP measurement was included. For analysesusing the evaluable (EVAL) data set, data from subjects, eyes or visitswith significant protocol deviations were excluded.

The primary and secondary IOP variables were summarized for eachtreatment at each study visit using means with 95% CIs, standarddeviations, minimums, medians and maximums. The primary and secondaryIOP variables were summarized similarly based on the difference betweentreatments within a subject. The calculations of mean and 95% CI of theIOP change from baseline for each treatment at Week 4 is considered theprimary analysis. All the other analyses are secondary analyses.

Interim results at week 8 (where n is the number of eyes), with the 3different plug placement configurations, showed IOP decreases frombaseline of −4.95 mmHg in Treatment group A (n=14), −4.31 mm Hg intreatment group B (n=14) and −6.07 mmHg in treatment group C (n=12).With the 95 μg dose comparing 3 different plug placement configurations(n=40), IOP decreases from baseline at Week 8 ranged from −4.31 mmHg to−6.07 mmHg.

Final Study Results: A total of 77 subjects enrolled in the study. Menand women were represented approximately evenly (47% and 53%,respectively). Most subjects were Caucasian (70%) or Black (25%), withan average age of 66 years. Most eyes were assessed to have open angleglaucoma (74%; of those, most were primary [98%]), while the other eyeshad ocular hypertension (26%). Mean IOP at screening was 18.02 mmHgoverall (18.3, 17.9, and 17.9 mmHg for eyes who received Treatment A, B,and C, respectively); by baseline (after the washout period) mean IOPhad increased to 25.39 mmHg overall (25.56, 25.00, and 25.61 mmHg foreyes who received Treatment A, B, and C, respectively).

At Week 4, 66 subjects (86%) had IOP measured; at Week 12, 49 subjects(64%) had IOP measured. A total of 53 subjects (69%) completed the study(Week 12),

The ITT data set included 154 eyes (53, 51, and 50 for Treatments A, B,and C, respectively), EVAL included 148 eyes (49, 51, and 48 forTreatments A, B, and C, respectively), and safety included all 77subjects. Six eyes were completely excluded from the EVAL analysis (botheyes of 3 subjects, 3 eyes from Treatment A and 3 from Treatment C), and2 additional eyes were excluded from Week 8 only (both eyes of 1subject, Treatments A and B); all eyes were excluded because ofconcomitant medication.

Treatment with L-PPDS resulted in significant mean IOP decreases frombaseline with all treatments across all time points (Table 8 and FIG.23)

TABLE 8 Summary of IOP (mmHg) Results (ITT Observed) Treatment ATreatment B Treatment Total Visit (N = 53) (N = 51) C (N = 50) (N = 154)Day 14 n 51 48 45 144 Mean IOP 20.16 19.98 20.04 20.06 Mean IOP ↓ −5.29−4.86 −5.35 −5.17 CI (−6.29, −4.28) (−5.67, −4.05) (−6.17, −4.53)(−5.67, −4.66) Week 4 n 45 46 41 132 Mean IOP 20.44 20.51 19.96 20.32Mean IOP ↓ −4.84 −4.38 −5.07 −4.75 CI (−6.01, −3.66) (−5.33, −3.43)(−6.11, −4.04) (−5.35, −4.15) Week 8 n 63 41 35 112 Mean IOP 20.53 20.6320.14 20.45 Mean IOP ↓ −4.65 −4.22 −4.88 −4.56 CI (−5.72, −3.58) (−5.18,−3.25) (−5.77, −3.99) −5.11, −4.01) Week 12 n 31 37 30 98 Mean IOP 20.4220.45 19.83 20.25 Mean IOP ↓ −4.34 −4.21 −5.06 −4.51 CI (−5.32, −3.37)(−5.33, −3.09) (−6.20, −3.93) (−5.12, −3.90)

Across time points after Day 1, Treatment C (95 μg L-PPDS lower punctum,blank plug upper punctum) resulted in the best mean IOP reductioncompared with the other treatment groups. Results for ITT observed dataincluding IOP after plug loss or removal (Table 8) were similar both tothe results for ITT observed data excluding IOP after plug loss orremoval and to EVAL data.

Retention rate of plugs in the lower puncta was ≥96% through Week 10 and92% at Week 12. Retention of upper plugs was 76%, 65%, and 58% at Weeks4, 8, and 12, respectively.

Study Conclusions: Treatment with L-PPDS (latanoprost dose of 95 μg/eye)resulted in a clinically meaningful and statistically significantreduction in IOP from baseline of approximately 5 mmHg after 4 weeks(primary endpoint). The configuration of a 95 μg L-PPDS in the lowerpunctum and a blank plug in the upper punctum (Treatment C) showef thebest IOP reduction of the three configurations investigated.

Example 7: Discussion and Final Analysis of GLAU 12 and GLAU 13 Studies

The primary endpoint in the Phase II studies was the mean change in IOPfrom baseline (measured as mmHg) at 4 weeks. Secondary endpoints werethe IOP change from baseline at other time points as well as the IOP andpercentage IOP change from baseline at all time points in the 12-weekstudy period.

A total of 57 ITT (Intent to Treat) subjects were included in the L-PPDStreatments in PPL GLAU 12, and a total of 77 ITT subjects were includedin L-PPDS treatments in PPL GLAU 13. See, FIG. 21. Two ITT datasets wereanalyzed, one including all IOP values regardless of plug loss, and theother, or second group, with IOP excluded after first plug loss/removal.FIG. 23 summarizes IOP changes from baseline at 4, 8 and 12 weeks forthe two studies for both ITT datasets. For both studies, mean IOPchanges from baseline were statistically significant at all time points.Across the 5 treatment arms of both studies, 3 arms showed clinicallysignificant IOP lowering of 5 mmHg or greater at 4 weeks for bothdatasets, and 2 arms showed clinically significant lowering of 5 mmHg orgreater at 4 and 6 weeks for one ITT dataset (IOP excluded after plugloss). One arm (the 95 μg lower/blank plug upper configuration(Treatment C)) showed a clinically significant IOP lowering ofapproximately 5.0 mmHg at 4, 8 and 12 weeks for both ITT datasets.

In GLAU 12, at the end of 4 weeks, the percentage of eyes with an IOPreduction vs baseline of 5 mmHg or greater was 70% for the 190 μg doseand 58% for the 141 μg dose. At 12 weeks these values were 45% of eyesat the 190 μg dose and 27% of eyes at the 146 μg dose (ITT observed datawith IOP excluded after first plug loss/removal). See FIG. 30.

In GLAU 13, at the end of 4 weeks, the percentage of eyes with an IOPreduction vs. baseline of 5 mmHg or greater was 58% for the blank pluglower/95 μg L-PPDS upper configuration (Treatment A), 50% for the openlower punctum/95 μg L-PPDS upper configuration (Treatment B), and 57%for the 95 μg L-PPDS lower/blank plug upper configuration (Treatment C);at 12 weeks these values were 52%, 59% and 66% for the threeconfigurations, respectively (ITT observed data with IOP excluded afterfirst plug loss/removal). See, FIG. 32.

During the 8-week second treatment course in GLAU 12 (n=38 eyes), theL-PPDS (190 μg) produced a statistically and clinically significantreduction in mean IOP at 4 and 6 weeks of 5.4 and 5.8 mmHg, respectivelyfor the all-observed IOP ITT dataset and 5.7 and 5.8 mm Hg, respectivelyfor the IOP excluded after plug loss ITT dataset. See FIG. 26. Upperplug retention was notably higher compared to the main study, achievingvalues of 90 and 88% at 4 and 8 weeks, respectively, for this shorterre-treatment course. See, FIG. 36

The 95 μg lower/blank upper configuration (Treatment C) demonstrated themost sustained IOP reduction (12 weeks) across all plug configurationsand doses, suggesting IOP lowering with the L-PPDS as currently designedmay be affected by the plug position (and tearing effects) of thesedesigns. See, FIGS. 27 and 28. Results of these studies also suggestthat double-plugging (simultaneous placement of both an upper and lowerplug) may be necessary to achieve a minimum IOP lowering effect usingthe current design configurations.

Data from the high dose study (PPL GLAU 12) demonstrated that higherdose levels of the current designs produced the largest mean IOP changefrom baseline at 4 weeks of all configurations across these two studies.However, higher doses alone did not result in a sustained effect beyond4 weeks, suggesting potentially different dose delivery mechanics withthe higher dose plugs. In addition, the high dose effects observed inthe repeat treatment phase of GLAU 12 (8 weeks at 190 ug for 19subjects) show differing effects between the first course (12 weeks) andsecond course (8 weeks). With the second treatment course of L-PPDS atthe 190 μg dose over 8 weeks, the IOP lowering effect was sustainedlonger, until 6 weeks (both ITT datasets)

In PPL GLAU 12, 2 subjects discontinued from the study due to AEs, 17discontinued due to plug loss, and 2 withdrew.

In PPL GLAU 13, 5 subjects discontinued from the study due to AEs, 14discontinued due to plug loss, 8 discontinued due to inadequate IOPcontrol and 1 withdrew.

Example 8: Retention Study (GLAU 11, 12 and 13 Studies)

A clinical study (Glau 11) was conducted to evaluate exemplaryembodiments of the present invention in comparison with a modifiedcommercial implant. The commercial implant 1000 is illustrated in FIGS.10A and 10B, where a side view and a top view are depicted respectivelyalong with corresponding major dimensions. The commercial implant 1000has no cavity. For the purpose of comparison study, the commercialimplant 1000 is modified by constructing a cavity 1002 in the implant1000, as shown in FIGS. 10C and 10D. The cavity 1002 is configured suchthat it has essentially the same shape and the same size as of thecavity 458 in the exemplary embodiments of the present inventionselected for the comparison study.

The comparison study involves ninety six subjects, baseline demographicsof which are provided in FIG. 11. Each subject is fitted with twomodified commercial implants indicated and two selected exemplaryembodiments of the present invention. The modified commercial implantsare referred as upper implants and the selected exemplary embodiments ofthe present application as lower implants. Both upper and lower implantscontain 141 μg of total latanoprotst drug stored in their respectivecavities. The 141 μg of total latanoprotst drug is consistent with threemonths of Xalatan drops.

The study was conducted over four weeks. During the study, the subjectswere examined and the intraocular pressure was checked weekly. Theobserved retention rate is plotted and illustrated in FIG. 9. In thestudy as well as in the present invention, the retention rate is definedas the percentage of eyes that retains implants over a certain period oftime. As indicated by the plot in FIG. 9, the selected exemplaryembodiments of the present invention achieves higher retention ratesthan the modified commercial implants. For example, while the retentionrate of the modified commercial implants declines to a rate below 60% inweek three, the retention rate of the selected exemplary embodiments ofthe present invention maintains at a relatively higher rate,approximately 95% or more, over the entire clinical trial. Having higherretention rate over a longer period of time is one of various advantagesof embodiments of the present invention.

Retention rates of different plug designs (FIG. 33) were also evaluatedin the GLAU 12 and 13 studies.

Retention rate by eye of plugs in the lower puncta was >95% through week12 in PPL GLAU 12 (FIGS. 34 and 35) and through week 10 in PPL GLAU 13(week 12 retention was 92%) (FIGS. 37 and 38). Retention of upper plugsby eye was 69%, 53% and 48% at weeks 4, 8 and 12, respectively, in PPLGLAU 12. In PPL GLAU 13, retention of upper plugs was 76%, 65% and 58%at weeks 4, 8 and 12, respectively. In addition, for eyes that retainedthe plugs past 4 weeks the rates the plugs were lost slowed, See FIG.39.

Upper plug retention with the proprietary punctal plugs was notablyimproved (approximately 19-33%) over the commercial plugs used in StudyPPL GLAU 11. At 4 weeks, the upper plug retention by eye had increasedfrom 48% in GLAU 11 to 67-81% in PPL GLAU 12 and PPL GLAU 13.

Upper plug retention was notably improved (by approximately 26%) overthe commercial plugs used in GLAU 11:

a. At 4 weeks:i. The upper plug retention increased from 45% in GLAU 11 to 71% for the141 μg total dose in GLAU 12ii. The upper plug retention for the higher 190 μg total dose wassimilar to improvements for the 141 μg dose, at 67%iii. The upper plug retention for the lower dose plug combinations (95μg) ranged from 77%-81% across the 3 treatment arms

At 8 weeks, 48%-69% upper plug retention across both studies

i. Upper plug retention for the 190 and 141 μg combinations ranged from48%-58% respectivelyii. Upper plug retention for the lower dose (95 μg) combinations rangedfrom 62%-69% across the 3 combinations

At 12 weeks, 42%-64% upper plug retention across both studies:

i. Upper plug retention for the 190 and 141 μg combinations ranged from42%-55% respectivelyii. Upper plug retention for the lower dose (95 μg) combinations rangedfrom 52%-64% across the three combinations

The above detailed description is intended to be illustrative, and notrestrictive. For example, the above-described examples (or one or morefeatures thereof) may be used in combination with each other. As anexample, one or more dimensions from the various implant embodimentsshown or described may be grouped together to form an implant embodimentcapable of providing a desired drug concentration. Other embodiments maybe used, such as by one of ordinary skill in the art upon reviewing theabove description. Also, in the above Detailed Description, variousfeatures may be grouped together to streamline the disclosure. Thisshould not be interpreted as intending that an unclaimed disclosedfeature is essential to any claim. Rather, inventive subject matter maybe in less than all features of a particular disclosed embodiment. Thus,the following claims are hereby incorporated into the DetailedDescription, with each claim standing on its own as a separateembodiment. The scope of the invention should be determined withreference to the appended claims, along with the full scope ofequivalents to which such claims are entitled.

The Abstract is provided to comply with 37 C.F.R. § 1.72(b), to allowthe reader to quickly ascertain the nature of the technical disclosure.It is submitted with the understanding that it will not be used tointerpret or limit the scope or meaning of the claims.

1. A kit for treating a patient with Open Angle Glaucoma (OAG) or OcularHypertension (OH) in an eye, comprising: a unit dosage format per eye ofa prostaglandin analog comprising a first lacrimal implant and a secondlacrimal implant, wherein the first lacrimal implant comprises asustained release formulation of a prostaglandin analog configured forrelease in a therapeutically effective dose from the first lacrimalimplant over a treatment period; and, wherein the second lacrimalimplant is a blank lacrimal implant that does not comprise aprostaglandin analog.
 2. The kit of claim 1, wherein the first or secondlacrimal implant is a punctual plug.
 3. The kit of claim 1, wherein thefirst or second lacrimal implant comprises a first member defining afirst axis and having a first end along the first axis; a second memberdefining a second axis and having a second end along the second axis;and a third member connecting the first end of the first member and thesecond end of the second member at a first angle to form an angledintersection.
 4. The kit of claim 3, wherein in the second member of thefirst or second lacrimal implant further comprises a cavity forinsertion of a drug core comprising the prostaglandin analog.
 5. The kitof claim 3, wherein the third member of the first or second lacrimalimplant further comprises a bore that is characterized by a third axisand a second angle, wherein the first angle is defined by the first axiswith respect to the second axis, the second angle is defined by thefirst axis with respective to the third axis, and the bore is configuredto be accessible to an insertion tool for facilitating insertion of theimplant.
 6. The kit of claim 3, wherein the lacrimal implant furthercomprises the prostaglandin analog dispersed throughout the implant. 7.The kit of claim 1, wherein the first or second lacrimal implant isconfigured with a retention rate of about 90% or greater at week 12 in alower punctum.
 8. The kit of claim 1, wherein the first or secondlacrimal implant is configured with a retention rate of about 85% orgreater at week 8 in the upper punctum.
 9. The kit of claim 1, whereinthe first or second lacrimal implant is made of a material thatcomprises a plastic, a rubber, a polymer, a composite or a material thatcomprises a liquid silicone rubber, or a mixture including a liquidsilicone rubber.
 10. The kit of claim 9, wherein the first or secondlacrimal implant further comprises a green colorant.
 11. The kit ofclaim 1, wherein the first or second lacrimal implant comprises a firstmember, a second member and a heel that is at least partially fabricatedwith silicone
 12. (canceled)
 13. (canceled)
 14. The kit of claim 1,wherein the first lacrimal implant is configured for insertion into anupper punctum of the eye.
 15. The kit of claim 1, wherein the secondlacrimal implant is configured for insertion into a lower punctum of theeye. 16-24. (canceled)
 25. The kit of claim 1, wherein the sustainedrelease formulation is configured to provide a dosage of theprostaglandin analog sufficient to reduce the intraocular pressure ofthe eye by at least 5 mm Hg from baseline for a continuous period oftime selected from at least 12 weeks after implantation of the firstlacrimal implant and second lacrimal implant.
 26. The kit of claim 1,wherein the treatment period is at least 4 weeks.
 27. The kit of claim1, wherein the treatment period is at least 8 weeks.
 28. The kit ofclaim 1, wherein the treatment period is at least 12 weeks.
 29. The kitof claim 1, further comprising an insertion tool.
 30. The kit of claim1, wherein the patient has a baseline TOP between about 22 mm Hg andabout 33 mm Hg.
 31. The kit of claim 1, wherein the first or secondlacrimal implant comprises a first member defining a first axis andhaving a first end along the first axis; a second member defining asecond axis and having a second end along the second axis; and a thirdmember connecting the first end of the first member and the second endof the second member at a first angle to form an angled intersection andwherein the third member of the lacrimal implant further comprises abore defining a third axis and a second angle having an upper surface,wherein the first angle is defined by the first axis with respect to thesecond axis, the second angle is defined by the first axis with respectto the third axis, and the bore is configured to be accessible to aninsertion tool for facilitating insertion of the implant and extendedfrom the upper surface into the third member.